Sulfasalazine

Pharmacological properties

in general, the drug and its metabolites exhibit immunomodulating properties, have an antibacterial effect, affect the arachidonic acid cascade and alter the activity of certain enzymes. the final clinical result is a decrease in the activity of the inflammatory process in the intestine. in rheumatoid arthritis, a modification of the course of the disease is observed after 1-3 months with a characteristic decrease in the level of srb and the values ​​of other indicators of inflammation. mesalazine (IU) is not considered as the cause of this effect.

Radiographic studies have shown a significant slowdown in the progression of the disease (according to the Larsen or Sharpe index) in patients at the early stages of the disease with sulfasalazine for 2 years compared with placebo or hydroxychloroquine. When the drug is canceled, the positive effect is significantly preserved.

Pharmacokinetics

Approximately 90% of the dose reaches the colon, where the drug is broken down by bacteria into sulfapyridine (SP) and mesalazine (ME). These compounds are also active; unsplit sulfasalazine (SASP) is also active in various symptoms. Most SPs are absorbed and subjected to hydroxylation or glucuronidation; in urine, a mixture of unchanged and metabolized SP is determined. A certain amount of ME undergoes acetylation in the wall of the colon, therefore, mainly AC-ME is excreted in the urine. SASP is excreted unchanged with bile and urine.

In studies of the use of EN tablets, no statistically significant difference was found between the values ​​of the main parameters of this dosage form and the equivalent dose of SASP in powder form; therefore, below are the data for conventional tablets. There is no evidence that when using Salazopyrin for the treatment of intestinal diseases, systemic concentrations have any effect that is different from adverse reactions. So, at SP concentrations above 50 μg / ml, the risk of adverse reactions increases significantly, especially in patients with a slow process of acetylation.

With oral administration of SASP in a single dose of 3 g C_max SASP in blood serum is reached after 3-5 hours; T_½ amounted to 5.7 ± 0.7 hours, the delay period was 1.5 hours. During the period of maintenance therapy, renal clearance of SASP was 7.3 ± 1.7 ml / min, for SP - 9.9 ± 1.9 ml / min and for AC-ME - 100 ± 20 ml / min. Free SP first appears in blood plasma 4.3 hours after a single dose; half-life is 2.7 hours. T_½ estimated to be 18 hours

ME: only AC-ME (non-free ME) was detected in urine; acetylation probably occurs to a large extent in the mucous membrane of the colon. After taking 3 g of SASP, the delay period was 6.1 ± 2.3 h, the levels of total ME in plasma were below 2 μg / ml. T_½ urine was 6.0 ± 3.1 hours, and the half-suction period, based on these data, was 3.0 ± 1.5 hours. The renal clearance constant was 125 ml / min, respectively, to the glomerular filtration rate.

There is no evidence that the kinetics of the drug in patients with rheumatoid arthritis will differ from the above.

Indications

Induction and maintenance of remission in ulcerative colitis; treatment of Crohns disease in the active stage.

Treatment of rheumatoid arthritis in adults in case of insufficient effectiveness of NSAIDs.

Treatment of juvenile polyarticular or oligosarticular rheumatoid arthritis.

Application

The dose is selected individually depending on the severity of the disease and tolerability of the drug. tablets should be swallowed whole, not broken or crushed.

Elderly patients: there are no special warnings.

Ulcerative colitis

Adults

Severe attack: 2–4 tablets of Salazopyrin 4 times a day, may be used in combination with steroids as part of an intensive care regimen.With the rapid passage of tablets, the effectiveness of the drug may decrease.

The night interval between doses should not exceed 8 hours.

Seizures of moderate severity: 2-4 tablets 4 times a day, it can be used in combination with steroids.

Mild seizures: 2 tablets 4 times a day with or without steroids.

Maintenance therapy: after the induction of remission, the dose is gradually reduced to 4 tablets per day. At this dose, the drug must be taken continuously, because when treatment is stopped, even a few years after an acute attack, the risk of relapse increases by 4 times.

Children. The dose is reduced in proportion to body weight. In case of acute attack or relapse: 40-60 mg / kg / day.

Maintenance therapy: 20-30 mg / kg / day.

Crohns disease

In Crohns disease in the acute stage, Salazopyrine-EN-tabs should be taken in the same way as with bouts of ulcerative colitis (see above).

Rheumatoid arthritis

Adults

In patients with rheumatoid arthritis and patients receiving NSAIDs for a long time, reactions from the stomach are possible, therefore, in the case of this disease, the drug Salazopyrin-EN-tabs is used according to the following recommendations. Treatment should be started with 1 tablet per day, gradually increasing the dose by 1 tablet per day every week, until the dose is 1 tablet 4 times a day or 2 tablets 3 times a day, depending on tolerability and effectiveness of the drug. The effect of the drug is manifested slowly and a pronounced effect may not be observed for 6 weeks. Improving joint mobility should be accompanied by a decrease in ESR and CRP. Possible simultaneous use of NSAIDs and Salazopyrine-EN-tabs.

Juvenile polyarticular or oligosarticular rheumatoid arthritis.

Children aged 2 years and older.

30-50 mg / kg / day, divided into 4 equal doses. Usually the maximum dose is 2000 mg / day. To reduce the possible adverse reaction from the gastrointestinal tract, one should start by taking ¼ the planned maintenance dose and then increase it by ¼ every week until the maintenance dose is reached.

Contraindications

Hypersensitivity to sulfasalazine, its metabolites or to other components of the drug, as well as to sulfonamides or salicylates; porphyria; age up to 2 years.

Side effects

In general, approximately 75% of cases of adverse reactions occur during the first 3 months of treatment, and more than 90% during the first 6 months. some adverse events are dose-dependent and often the manifestation of symptoms can be reduced by lowering the dose of the drug.

Are common

Sulfasalazine is broken down by intestinal bacteria to sulfapyridine and 5-aminosalicylate, therefore adverse reactions to sulfonamide or salicylate are possible. Patients with slow acetylation status are more likely to experience adverse reactions to sulfapyridine. The most common adverse reactions are nausea, headache, rash, lack of appetite, and fever.

Specific

Adverse reactions observed in clinical trials of sulfasalazine are listed below by class and frequency (very common (≥1 / 10); often (≥1 / 100 - 1/10); infrequently (≥1 / 1000 1/100). In cases where an adverse reaction was noted at different rates in clinical trials, the highest of the frequencies reported was indicated. Additional reactions that were reported in the post-marketing period are also included in the list below with a frequency of “unknown” (the frequency cannot be determined from the available data).

Infections and infestations: unknown - pseudomembranous colitis.

From the blood system and lymphatic system: often - leukopenia; rarely - thrombocytopenia (for details, see SPECIAL INSTRUCTIONS); unknown - agranulocytosis, aplastic anemia, hemolytic anemia, anemia with Heinz bodies, hypoprothrombinemia, lymphadenopathy, macrocytosis, megaloblastic anemia, methemoglobinemia, neutropenia, pancytopenia.

On the part of the immune system: unknown - anaphylaxis, nodular polyarteritis, serum sickness.

From the side of metabolism and nutrition: unknown - loss of appetite.

Mental disorders: often - insomnia; infrequently - depression; unknown - hallucinations.

From the nervous system: often - dizziness, headache, change in taste sensations; rarely - cramps; unknown - aseptic meningitis, ataxia, encephalopathy, peripheral neuropathy, violation of smell.

On the part of the organ of hearing and the labyrinth: often - ringing in the ears; infrequently - vertigo.

From the side of the organ of vision: often - injection of conjunctiva and sclera.

From the side of the heart: unknown - allergic myocarditis, cyanosis, pericarditis.

From the vascular system: infrequently - vasculitis.

From the respiratory system, chest and mediastinal organs: often - cough; infrequently - dyspnea, unknown - fibrous alveolitis, eosinophilic infiltration, interstitial lung disease.

From the gastrointestinal tract: very often - upset stomach, nausea; often - abdominal pain, diarrhea, vomiting, stomatitis; unknown - exacerbation of ulcerative colitis, pancreatitis, mumps.

On the part of the liver: unknown - liver failure, fulminant hepatitis, hepatitis (for details see SPECIAL INSTRUCTIONS).

On the part of the skin and subcutaneous tissue: often - itching; infrequently - alopecia, urticaria; unknown - epidermal necrolysis (Lyell syndrome), Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis, erythema, exanthema, exfoliative dermatitis, periorbital edema, lichen planus, photosensitivity.

From the musculoskeletal system and connective tissue: often - arthralgia; unknown - systemic lupus erythematosus.

From the urinary system: often - proteinuria; unknown - nephrotic syndrome, interstitial nephritis, crystalluria (for details see SPECIAL INSTRUCTIONS), hematuria.

From the reproductive system and mammary glands: reversible oligospermia (for details, see SPECIAL INSTRUCTIONS).

General condition and disorders associated with the method of use of the drug: often - fever; rarely - swelling of the face; unknown - staining of the skin and body fluids in yellow.

Research: infrequently - increased activity of liver enzymes; unknown - induction of autoantibodies.

special instructions

Prior to the start of therapy and during the first 3 months of treatment, all patients should be monitored for a detailed blood count (including white blood cell count), and liver and kidney function tests (including urinalysis). in the future, these indicators are controlled according to clinical indications. patients should be warned about the need to immediately consult a doctor if there are clinical signs such as sore throat, fever, malaise, pallor, purpura, jaundice or a sudden nonspecific disease during treatment with sulfasalazine, which may indicate myelosuppression, hemolysis or hepatotoxicity. in the presence of these signs, treatment with sulfasalazine should be discontinued until the results of a blood test are obtained.

Sulfasalazine should not be prescribed to patients with impaired liver or kidney function or with pathological changes in the blood, unless the potential benefit outweighs the risk.

Sulfasalazine should be prescribed with caution to patients with severe allergies or AD.

The use of the drug in the treatment of children with a systemic form of juvenile rheumatoid arthritis often causes reactions similar to serum sickness, therefore sulfasalazine is not recommended for these patients.

Since sulfazalazine can cause the development of hemolytic anemia, it should be used with caution in patients with glucose-6-phosphate dehydrogenase deficiency.

Sulfasalazine, when administered orally, slows down the absorption and metabolism of folic acid, which can lead to a deficiency and lead to serious blood disorders (e.g. macrocytosis and pancytopenia), the patients condition can be normalized with folic or folinic acid (leucovorin).

Since sulfasalazine causes crystalluria and the formation of calculi in the kidneys, a sufficient amount of fluid should be consumed during treatment.

In men treated with sulfasalazine, oligospermia and infertility are possible.After discontinuation of sulfasalazine therapy, these effects disappear within 2–3 months.

During pregnancy and breastfeeding.

Pregnancy

According to published data on the use of sulfasalazine in pregnant women there is no evidence of the risks of teratogenic effects. The probability of a negative effect on the fetus when using sulfasalazine during pregnancy is low. When taken orally, sulfasalazine inhibits the absorption and metabolism of folic acid and can lead to folic acid deficiency. Since the negative effect cannot be completely ruled out, during pregnancy, sulfasalazine is prescribed only in case of emergency.

Lactation

Small amounts of sulfasalazine and sulfapyridine are determined in breast milk, therefore, the drug should be used with caution during breastfeeding, especially in the case of premature infants and glucose-6-phosphate dehydrogenase deficiency. The decision to stop breastfeeding or to discontinue the drug is made by the attending physician on the basis of a thorough assessment of the benefit for mother / risk for the baby.

Children. The drug is contraindicated in children under the age of 2 years. The use of the drug in the treatment of children with a systemic form of juvenile rheumatoid arthritis often causes reactions similar to serum sickness, therefore sulfasalazine is not recommended for these patients.

Influence on the ability to drive vehicles or work with other mechanisms. The effect of sulfasalazine on the reaction rate when driving vehicles or working with other mechanisms has not been systematically evaluated.

Interactions

A decrease in digoxin absorption was reported, which led to subtherapeutic concentrations of the latter in blood serum, with its simultaneous use with the oral form of sulfasalazine.

The chemical properties of sulfonamides have a certain similarity with some oral hypoglycemic drugs. In patients taking sulfonamides, hypoglycemia was observed. It is necessary to carefully monitor the condition of patients taking sulfasalazine and hypoglycemic agents.

Since sulfasalazine inhibits thiopurinmethyltransferase, the simultaneous use of oral salazopyrine and thiopurin-6-mercaptopurine or its preparations (azathioprine) may inhibit bone marrow function and the development of leukopenia.

The simultaneous use of sulfasalazine and methotrexate in patients with rheumatoid arthritis does not change the pharmacokinetic characteristics of the drugs. However, an increase in the frequency of adverse reactions from the gastrointestinal tract, in particular nausea, was reported.

Overdose

In the absence of increased sensitivity, acute toxicity of the drug with oral administration is low. there is no specific antidote, supportive treatment should be carried out.

Storage conditions

At a temperature not exceeding 25 ° C.