Pasch sodium salt

INSTRUCTIONS for medical use of the medicinal product PASC sodium salt (PASC sodium salt)

Composition:

Active substance: sodium para-aminosalicylate dihydrate;

One sachet contains 5.52 g of sodium para-aminosalicylate dihydrate, corresponding to 4.00 g of para-aminosalicylic acid;

Excipients: lactose monohydrate, aspartame (E 951).

Pharmaceutical form. Powder for oral solution.

Main physico-chemical characteristics: powder of almost white to off-white color, slight color variation may occur.

Pharmacotherapeutic group. Antituberculosis agents. ATC code J04A A02.

Pharmacological properties.

Pharmacodynamics.

Sodium para-aminosalicylate has bacteriostatic activity against Mycobacterium tuberculosis and belongs to reserve anti-tuberculosis agents. The bacteriostatic effect of the drug is associated with competition between aminosalicylic acid and structurally similar aminobenzoic acid in the process of folic acid synthesis, which is essential for the growth and reproduction of Mycobacterium tuberculosis. Aminosalicylic acid is incorporated instead of aminobenzoic acid into the folic acid synthesis pathway, thereby disrupting normal RNA, DNA, and protein synthesis in Mycobacterium tuberculosis. In order for sodium para-aminosalicylate to displace aminobenzoic acid, it must be administered in large doses. Sodium para-aminosalicylate does not affect other microorganisms. The activity of sodium para-aminosalicylate against Mycobacterium tuberculosis is lower compared to that of first-line anti-tuberculosis drugs; therefore, sodium para-aminosalicylate is used in combination with other, more effective anti-tuberculosis agents. When used as monotherapy, resistance of Mycobacterium tuberculosis to sodium para-aminosalicylate develops rapidly. With combination therapy, resistance develops more slowly.

Pharmacokinetics.

After oral administration, sodium para-aminosalicylate is well absorbed in the gastrointestinal tract. Sodium para-aminosalicylate is better absorbed than para-aminosalicylic acid. Following oral administration of a dose of sodium para-aminosalicylate equivalent to 4 g of para-aminosalicylic acid, maximum plasma concentration of approximately 75 mg/mL is achieved within 0.5–1 hour. Only 15% of the administered dose is bound to plasma proteins. The active substance rapidly distributes into tissues and body fluids (including peritoneal, pleural, and synovial fluids), where concentrations do not significantly differ from those in plasma. Concentrations in cerebrospinal fluid are low; active substance levels increase only in the presence of meningeal inflammation. Sodium para-aminosalicylate crosses the placental barrier and is excreted in breast milk. Approximately 50% of the active substance is metabolized in the liver via acetylation, forming inactive metabolites. The elimination half-life is 1 hour. In case of impaired renal function, the elimination half-life is prolonged up to 23 hours. About 85% of the dose is excreted in urine via glomerular filtration and tubular secretion within 7–10 hours. Of the administered dose, 14–33% is excreted unchanged and 50% as metabolites.

Clinical characteristics.

Indications.

In combination therapy for active progressive forms of tuberculosis, primarily chronic fibro-cavitary pulmonary tuberculosis.

Contraindications.

• Hypersensitivity to the active substance or to excipients of the medicinal product;
• severe hepatic insufficiency, hepatitis, liver cirrhosis;
• severe renal insufficiency;
• marked left ventricular myocardial hypertrophy;
• decompensated heart failure;
• peptic ulcer of the stomach and duodenum;
• myxedema;
• amyloidosis;
• pregnancy and breastfeeding period.

The composition of PAS sodium salt powder includes the sweetener aspartame. The use of aspartame is contraindicated in patients with phenylketonuria.

Interaction with medicinal products and other types of interactions.

In the treatment of tuberculosis, several medicinal products with different mechanisms of action against Mycobacterium tuberculosis are used simultaneously. In combination therapy, the development of bacterial resistance is slowed, and mutual enhancement of drug effects occurs.

PAS sodium salt delays the development of resistance of Mycobacterium tuberculosis to isoniazid and streptomycin. When PAS sodium salt is combined with isoniazid, the concentration of isoniazid in blood increases, increasing the risk of hemolytic anemia.

The efficacy of PAS sodium salt is reduced when used concomitantly with aminobenzoates.

When the medicinal product is used concomitantly with anticoagulants, the anticoagulant effect is enhanced because PAS sodium salt inhibits hepatic synthesis of prothrombin.

Probenecid (a uricosuric agent) delays the urinary excretion of PAS sodium salt, resulting in increased plasma concentration and an increased risk of toxicity (dose reduction is required).

Absorption of vitamin B12 may be reduced by para-aminosalicylic acid, leading to clinically significant reductions in erythrocyte count due to decreased vitamin B12 levels. Therefore, for patients receiving this therapy for more than one month, vitamin B12 supplementation should be considered.

When PAS sodium salt is used concomitantly with hypoglycemic agents, hypoglycemia in blood is enhanced.

Hypokalemia may develop when PAS sodium salt is used with capreomycin or when high doses of PAS sodium salt are used in elderly patients with peripheral edema and arterial hypertension.

The medicinal product interferes with absorption and reduces the efficacy of rifampicin, erythromycin, and lincomycin.

Para-aminosalicylic acid may reduce gastrointestinal absorption of digoxin by inhibiting the absorptive function of intestinal cells. In patients receiving concomitant therapy, serum digoxin levels should be monitored.

Antacid agents do not interfere with drug absorption.

When iodine-containing thyroid hormones, their analogs, and antagonists (including antithyroid agents) are used, it should be noted that PAS sodium salt therapy alters the concentrations of T4 and TSH in blood.

Ammonium chloride increases the risk of crystalluria.

Concomitant use of para-aminosalicylic acid and ethionamide may intensify adverse reactions of para-aminosalicylic acid, primarily affecting the gastrointestinal tract, including jaundice, hepatitis, nausea, vomiting, diarrhea, abdominal pain, or anorexia. Ethionamide should be discontinued if these reactions are severe.

Diphenhydramine reduces gastrointestinal absorption of para-aminosalicylic acid and should not be administered concurrently.

Adverse effects of the medicinal product and salicylates are additive.

Drug interaction studies in HIV-infected patients receiving antiretroviral agents and para-aminosalicylic acid have not been conducted. Given the metabolic pathway of para-aminosalicylic acid, significant drug interactions are not expected.

Special precautions for use

Use with caution in patients with gastrointestinal disorders, hepatic or renal dysfunction, and heart failure (in cases of severe impairment, use is contraindicated).

Use with caution in patients with severe atherosclerosis and thrombophlebitis.

Hepatotoxicity

Para-aminosalicylic acid may cause hepatitis. Initial symptoms usually appear within three months after initiation of therapy and most commonly include rash, followed by fever and, less frequently, gastrointestinal disturbances such as anorexia, nausea, or diarrhea. In such cases, treatment must be discontinued immediately.

If signs of hepatitis occur, sodium PAS should be replaced with ethambutol.

Hypersensitivity

The patient must be under close observation during the first three months of therapy. Treatment must be discontinued immediately at the first signs of rash, fever, or other manifestations of intolerance.

Hypothyroidism

Prolonged use of high doses of the drug, as well as concomitant use with ethionamide, may lead to decreased thyroid function. Hypothyroidism can be managed with levothyroxine replacement therapy without discontinuation of anti-tuberculosis treatment. This effect of sodium PAS should be taken into account in patients with tuberculosis who also have hypofunction of the thyroid gland.

Hypothyroidism in patients concurrently infected with HIV

Para-aminosalicylic acid increases the risk of hypothyroidism in patients concurrently infected with HIV. Thyroid function should be monitored in HIV-infected patients before initiation of treatment and regularly during treatment, especially if para-aminosalicylic acid is administered concurrently with ethionamide/prothionamide.

Crystalluria may occur during administration of sodium PAS. Its development is slowed when urine pH is neutral or alkaline.

Impaired blood coagulation may occur during use of the drug.

Use with caution in patients at risk of bleeding from any cause.

Due to the risk of developing hemolytic anemia, use with caution in patients with glucose-6-phosphate dehydrogenase deficiency.

Sodium PAS is not recommended for patients on a low-sodium diet.

Periodically perform blood and urine analyses and monitor liver function tests.

The medicinal product contains lactose monohydrate and therefore should not be used in patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

The medicinal product also contains aspartame, which is a source of phenylalanine. This may be harmful for patients with phenylketonuria.

Smoking and alcohol consumption are not permitted during treatment.

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of para-aminosalicylic acid in pregnant women are lacking or limited. Animal studies have shown some reproductive toxicity.

Sodium PAS is contraindicated during pregnancy and in women of childbearing potential who are not using effective contraception.

Scientific reports on the use of para-aminosalicylic acid in pregnant women always describe concomitant use of other medicinal products. Since there are no reliable and well-controlled studies on the effects of para-aminosalicylic acid in humans, para-aminosalicylic acid should not be administered to pregnant women.

Breastfeeding

Sodium PAS is excreted in breast milk. Information on the effects of para-aminosalicylic acid on newborns/infants is insufficient.

The use of sodium PAS during breastfeeding is contraindicated.

Ability to affect reaction speed when driving or operating machinery

The medicinal product does not affect reaction speed when driving or operating machinery. However, patients who develop symptoms of hepatic encephalopathy during treatment should exercise caution.

Administration and Dosage

Sodium PAS is administered only in combination with other medicinal products for the treatment of tuberculosis.

To reduce irritation of the gastric mucosa, the medicinal product should be taken after meals. The contents of the sachet should be dissolved by stirring in 100 mL (half a glass) of water. The prepared solution should be taken immediately.

Adults: The recommended dose is 8–12 g per day. The daily dose should be divided into 2–3 doses.

For patients with body weight less than 50 kg, as well as in cases of poor tolerance, the dose should be reduced to 4–8 g per day.

Maximum daily dose – 12 g.

Children: The recommended dose is 200–300 mg/kg body weight per day, divided into 2–4 doses.

Patients with renal impairment (creatinine clearance <30 mL/min): The dose is up to 8 g (in 2 doses).

Patients with hepatic impairment: Dose reduction is not required; however, liver function parameters should be monitored during treatment.

Elderly patients

There is no information regarding the use of sodium PAS for the treatment of elderly patients.

Children

There is no information regarding restrictions on the use of the medicinal product in children.

Overdose

Symptoms: Nausea, vomiting, diarrhea; psychosis may develop.

Treatment is symptomatic. Activated charcoal should be administered to delay absorption, gastric lavage should be performed, and vital functions should be monitored.

Adverse Reactions

Classification of adverse reactions by frequency of occurrence: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).

From the nervous system: rare – hepatic encephalopathy (including confusion, drowsiness), headache, optic neuritis, paresthesia, fear; very rare – tendon pain, visual disturbances, peripheral neuropathy, dizziness; common – nausea, vestibular syndrome.

From the blood and lymphatic system: very rare – leukopenia, methemoglobinemia, hemolytic anemia (in patients with glucose-6-phosphate dehydrogenase deficiency), impaired synthesis of prothrombin, thrombocytopenia, purpura, agranulocytosis, eosinophilia.

From the immune system: rare – hypersensitivity reactions (fever, bronchospasm, eosinophilic lung infiltrate, Löffler’s syndrome), anaphylactic shock.

From the heart: frequency not known – pericarditis.

From the vascular system: rare – vasculitis, arterial hypertension, fluctuations in blood pressure.

From the gastrointestinal tract: common – dyspeptic symptoms, worsening or loss of appetite, nausea, vomiting, stomach and/or epigastric pain, discomfort in the abdominal area, diarrhea or constipation, flatulence, changes in bowel movements; uncommon – anorexia; rare – malabsorption syndrome (see "Description of specific adverse reactions" below), peptic ulcer, gastrointestinal bleeding, jaundice, metallic taste in the mouth.

If these adverse reactions occur, the dose should be reduced or the drug temporarily discontinued.

Adverse reactions are milder if the patient adheres to a proper three-meal-a-day diet.

From the liver and/or biliary system: rare – jaundice, hepatitis, enlargement and tenderness of the liver.

From the kidneys and urinary system: rare – crystalluria.

From the skin and subcutaneous tissues: common – skin hypersensitivity, skin rashes; rare – dermatitis (urticaria or purpura), exanthema, exfoliative dermatitis, enanthema; frequency not known – itching.

From the musculoskeletal and connective tissue system: rare – joint pain, myalgia.

From metabolism and nutrition: rare – hypothyroidism (see "Description of specific adverse reactions" below); very rare – hypokalemia (observed during prolonged use in patients with cardiovascular disorders), hypoglycemia.

General disorders: frequency not known – asthenia, general body pain.

Investigations: very rare – decreased prothrombin levels, hepatic cytolysis, increased blood levels of alkaline phosphatase, transaminases, weight loss.

In case of allergic reactions, the patient should consult a physician regarding discontinuation of the drug.

Description of specific adverse reactions

Hypothyroidism

Hypothyroidism occurs very commonly (in ≥ 1/10 patients) in patients co-infected with HIV, especially when sodium PAS is used concomitantly with ethionamide/prothionamide.

Malabsorption syndrome

Malabsorption syndrome may develop in patients taking para-aminosalicylic acid, but it usually does not manifest fully. Full manifestation of the syndrome includes: steatorrhea, small intestine abnormalities on X-ray, villous atrophy, decreased cholesterol levels, reduced absorption of D-xylose and iron. Triglyceride absorption is always normal.

If any adverse reactions not listed in this instruction appear during treatment, or if any of the listed adverse reactions are particularly severe, the patient should consult a physician.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30°C.

Keep out of reach of children.

Packaging.

12.5 g of the drug per laminated sachet. 25 or 300 sachets per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

JSC "Olfa" / Olpha AS.

Manufacturer's address and place of business.

Rupnicu iela 5, Olaine, Olaines novads, LV-2114, Latvia.