Tetramax

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TETRAMAX (TETRAMAX)

Composition:

Active substance: tetracycline hydrochloride;

1 capsule contains tetracycline hydrochloride 500 mg, calculated as 100% anhydrous substance;

Excipients: lactose monohydrate, magnesium stearate;
hard gelatin capsule: gelatin, azorubine (E122), indigo carmine (E132), titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172).

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules of cylindrical shape with hemispherical ends; the body is pink, the cap is burgundy. The capsule contents are a powder ranging from yellow to yellowish-brown; the presence of agglomerate particles (a cluster of particles firmly held together) is acceptable.

Pharmacotherapeutic group. Antibacterials for systemic use. Tetracyclines. ATC code J01AA07.

Pharmacological Properties

Pharmacodynamics

Bacteriostatic antibiotic of the broad-spectrum tetracycline group. Inhibits protein synthesis by blocking the binding of aminoacyl-transfer RNA (tRNA) to the "messenger RNA (mRNA) — ribosome" complex. Active against Gram-positive bacteria (Staphylococcus spp., including penicillinase-producing strains; Streptococcus spp., including Streptococcus pneumoniae; Haemophilus influenzae, Listeria spp., Bacillus anthracis) and Gram-negative microorganisms (Neisseria gonorrhoeae, Bordetella pertussis, Escherichia coli, Enterobacter spp., Klebsiella spp., Salmonella spp., Shigella spp.), as well as Rickettsia spp., Chlamydia spp., Mycoplasma spp., Treponema spp., Borrelia spp., Vibrio cholerae, Chlamydophila psittaci, Francisella tularensis, Campylobacter, Bartonella. Resistant to the drug's action: Pseudomonas aeruginosa, Proteus spp., Serratia spp., most strains of Bacteroides spp., fungi, and small viruses.

Pharmacokinetics

One hour after intravenous administration or rapid infusion of a single 500 mg dose of tetracycline hydrochloride, its plasma concentration reaches 4–5 mg/L. With repeated administration at 12-hour intervals, some accumulation occurs, resulting in average plasma concentrations of tetracycline of 6.4 mg/L.

Following oral administration of 500 mg tetracycline hydrochloride, maximum plasma concentrations are achieved within 2 hours and average 3.0–4.3 mg/L after a single dose. After repeated oral doses of 500 mg in adults with normal liver function, steady-state plasma concentrations of tetracycline reach 1.5–4.3 mg/L. However, increasing the dose does not result in a proportional increase in plasma concentration.

The bioavailability of tetracycline after oral administration in fasting adults is 75–80%.

In adults with normal renal function, the elimination half-life from plasma is 8–9 hours, although it may be significantly prolonged in patients with renal impairment, depending on the degree of kidney damage. Plasma protein binding ranges from 36% to 64%.

Tetracycline hydrochloride is only slightly absorbed after intramuscular injection, resulting in lower plasma concentrations compared to oral administration.

Intestinal absorption may be significantly reduced when taken simultaneously with certain foods or medications. In particular, polyvalent cations such as iron, manganese, magnesium, and calcium can form non-absorbable chelate complexes with tetracycline.

Tetracycline is well distributed into tissues, particularly the liver, gallbladder, kidneys, bones, teeth, genital organs, and nasal mucosal membranes. Effective concentrations are also achieved in various body fluids (pleural, pericardial, peritoneal, and synovial fluids). On the other hand, it is present in cerebrospinal fluid only in low concentrations, amounting to only 10–30% of plasma levels, even during inflammation of the meninges.

Tetracycline accumulates in the liver. It is excreted into the gastrointestinal tract via bile and partially reabsorbed (enterohepatic circulation).

Approximately 30–50% of tetracycline is metabolized, while 30–70% is excreted unchanged in urine. It undergoes dialysis to a minimal extent, and peritoneal dialysis is ineffective.

Clinical characteristics.

Indications.

The medicinal product is indicated for infectious and inflammatory diseases caused by microorganisms sensitive to tetracycline hydrochloride, such as:

• Infections of the upper respiratory tract.
• Infections of the lower respiratory tract.
• Rickettsioses, including Rocky Mountain spotted fever, typhus group infections, and Q fever.
• Psittacosis.
• Trachoma.
• Granuloma inguinale.
• Relapsing fever borreliosis — as part of combination therapy.
• Bartonellosis.
• Tularemia.
• Cholera.
• Brucellosis.
• Campylobacteriosis — as part of combination therapy.
• Urinary tract infections.
• Other infections caused by susceptible gram-negative organisms.
• Severe forms of acne — as part of combination treatment.

When penicillin is contraindicated, tetracycline may be used as an alternative agent for the treatment of the following infections:

• Syphilis.
• Gonorrhea.

Contraindications.

Hypersensitivity to tetracycline hydrochloride and related antibiotics, local anesthetics (lidocaine, procaine); fungal infections, systemic lupus erythematosus. Pregnancy. Lactation. Patient age under 12 years. Liver and kidney diseases with pronounced functional insufficiency.

Cases of benign intracranial hypertension have been reported with concomitant use of tetracyclines and vitamin A or retinoids; therefore, their simultaneous use is contraindicated.

Interaction with other medicinal products and other forms of interaction.

Iron salts, oral zinc, calcium, bismuth (incl. bismuth subsalicylate), aluminum, magnesium, and other preparations containing these cations (incl. magnesium-containing laxatives, antacids, sucralfate), cholestyramine, colestipol, kaolin-pectin, sodium bicarbonate: formation of inactive tetracycline chelates and reduced tetracycline absorption. Combinations with these agents should be avoided, as well as with quinapril (contains magnesium carbonate) and didanosine (contains calcium- and magnesium-containing excipients). If such combination is necessary, tetracycline should be administered at least 2 hours before or 4–6 hours after administration of these agents.

Strontium ranelate: possible reduction in tetracycline serum concentration. Concomitant use should be avoided. It is recommended to interrupt strontium ranelate treatment during tetracycline therapy.

Digoxin, lithium preparations: possible increase in their serum concentrations.

Ergotamine and methysergide: increased risk of ergotism.

Penicillins, cephalosporins, beta-lactam antibiotics: as a bacteriostatic antibiotic, tetracycline may interfere with the bactericidal activity of other antibiotics. Such combinations should be avoided.

The combination of tetracycline with oleandomycin and erythromycin is considered synergistic.

Indirect anticoagulants, incl. warfarin, phenindione, antithrombotic agents: tetracyclines may enhance the effect of indirect anticoagulants due to inhibition of their hepatic metabolism, reduce plasma prothrombin levels, requiring careful monitoring of prothrombin time and, if necessary, reduction of anticoagulant dose.

Atovaquone: reduced plasma concentration of atovaquone.

Methoxyflurane: possible nephrotoxic effects (incl. increased blood urea nitrogen and serum creatinine levels), acute renal failure, sometimes fatal.

Methotrexate: possible increase in its toxicity; this combination should be used with caution. Regular monitoring of toxicity is required if simultaneous administration is necessary.

Vitamin A and retinoids, such as acitretin, isotretinoin, and tretinoin (for acne treatment), when used concomitantly with tetracyclines, may cause benign intracranial hypertension; therefore, their simultaneous use is contraindicated. To prevent this complication during acne treatment with retinoids, an interval should be maintained after tetracycline therapy.

Hormonal contraceptives: reduced efficacy (unplanned pregnancy) and increased frequency of breakthrough bleeding when used with tetracyclines. Therefore, non-hormonal contraceptive methods are recommended during tetracycline treatment and for 7 days after completion of therapy.

Diuretics: such combination requires caution, as dehydration increases the risk of nephrotoxicity.

Antidiabetic agents (insulin, sulfonylureas, incl. glibenclamide, glipizide): enhanced hypoglycemic effect.

Chymotrypsin increases tetracycline concentration and duration of circulation in blood.

Tetracycline should be administered with caution together with hepatotoxic agents.

Oral typhoid vaccine, BCG vaccine: antibacterial agents, incl. tetracyclines, may reduce the therapeutic efficacy of these vaccines. Vaccination should be avoided during antibiotic treatment.

Tetracycline absorption is impaired when administered during meals, with milk, and dairy products.

Special precautions for use.

Esophagitis. Cases of esophagitis and esophageal ulcers have been reported in patients taking encapsulated or tablet forms of tetracyclines. The drug should be taken with a sufficient amount of liquid and swallowed in an upright position (sitting or standing), well before bedtime. If symptoms such as dysphagia or substernal pain occur, the possibility of this complication should be considered and discontinuation of the drug should be evaluated. Tetracycline should be used with caution in patients with esophageal reflux.

Photosensitization. Cases of photosensitivity reactions with clinical manifestations of severe sunburn have been reported in patients taking tetracyclines. During treatment, patients should protect exposed areas of skin from direct sunlight and artificial UV radiation. Patients should be informed about the possibility of such reactions and advised to discontinue tetracycline therapy immediately upon the first signs of skin erythema.

Due to the potential development of photodermatoses (increased photosensitivity associated with tetracycline antibiotics), the drug should not be used during exposure to sunlight or UV irradiation.

Microflora. Antibiotic use may lead to overgrowth of non-susceptible microorganisms, including fungi such as Candida, and to the development of superinfection, which may require discontinuation of the antibiotic and appropriate intervention.

To prevent candidiasis, concomitant use of antifungal agents and vitamins is recommended during tetracycline therapy.

Diarrhea, particularly severe, persistent, and/or with blood, during or after treatment (including several weeks after completion of therapy) with tetracycline may be a symptom of Clostridium difficile-associated diarrhea (CDAD). The severity of CDAD may range from mild diarrhea to life-threatening pseudomembranous colitis.

CDAD should be considered in all patients who develop severe diarrhea during or after antibiotic use.

Tooth development. The use of tetracyclines during tooth development (second and third trimesters of pregnancy, breastfeeding period, neonatal period, and childhood up to 12 years of age) may cause permanent discoloration of teeth (yellow-brown-gray). This adverse reaction is more common with prolonged use but may also occur after repeated short courses of treatment. Reports of enamel hypoplasia have also been documented.

Venereal diseases. Tetracyclines may mask the symptoms of syphilis. When treating venereal diseases with suspected coexisting syphilis, appropriate diagnostic procedures should be performed. In all such cases, monthly serological tests should be conducted for at least 4 months.

Beta-hemolytic streptococci. For infections caused by group A beta-hemolytic streptococci, treatment should last for at least 10 days.

Myasthenia gravis. The drug should be used with caution in patients with myasthenia gravis due to the potential for neuromuscular blockade.

Systemic lupus erythematosus, porphyria. Tetracyclines may exacerbate systemic lupus erythematosus. Rare cases of porphyria have been reported in patients receiving tetracyclines. Therefore, tetracycline should not be used in patients with porphyria or systemic lupus erythematosus.

Renal function impairment. The use of tetracycline is generally contraindicated in renal insufficiency due to the risk of excessive accumulation and increased likelihood of adverse effects.

Antianabolic effect of tetracyclines may lead to elevated blood urea nitrogen levels. While this is not significant in patients with normal renal function, in patients with severely impaired renal function, high serum levels of tetracycline may result in azotemia, hyperphosphatemia, and acidosis.

Hepatic function impairment. Tetracycline should be used with caution in patients with hepatic dysfunction and in those receiving potentially hepatotoxic drugs. High doses should be avoided. High-dose tetracycline use has been associated with fatty infiltration of the liver and pancreatitis.

Tetracycline hydrochloride should be prescribed with caution in patients with leukopenia.

Since tetracyclines reduce plasma prothrombin activity, patients on anticoagulant therapy may require a reduction in anticoagulant dosage.

During prolonged treatment, periodic blood tests, renal and liver function tests should be performed.

Tetracycline therapy should be administered under medical supervision. The prescribed regimen must be strictly followed throughout the treatment course, without missing doses and taking them at regular intervals. If a dose is missed, it should be taken as soon as possible; however, if the next dose is due soon, the missed dose should be skipped—do not double the dose. Tetracycline hydrochloride should not be taken simultaneously with milk or other dairy products, as this impairs its absorption.

If signs of hypersensitivity or adverse reactions occur, the drug should be discontinued; if necessary, another antibiotic (not from the tetracycline group) should be prescribed. To prevent possible complications, concomitant use of hepatoprotectors, choleretics, eubiotics, vitamins, and antifungal agents may be advisable.

Tetracycline is not the drug of choice for the treatment of any type of staphylococcal infection.

Prescribing the drug to adults at doses below 800 mg per day is not recommended, as it may result not only in insufficient therapeutic effect but also in the development of tetracycline-resistant microbial strains.

The medicinal product contains lactose; therefore, if the patient has known sugar intolerance, medical advice should be sought before taking the drug.

The medicinal product contains the colorant azorubine (E122), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Tetracyclines cross the placenta and may have toxic effects on fetal tissues, particularly on skeletal development; therefore, the drug is contraindicated during pregnancy.

Tetracyclines are excreted in breast milk and are therefore contraindicated during breastfeeding.

All tetracyclines form stable calcium complexes in any calcifying tissue (skeletal bone, tooth enamel, dentin). Reduced growth rate of the tibia has been observed in premature infants receiving oral tetracycline at doses of 25 mg/kg every 6 hours. This adverse reaction was reversible upon discontinuation of the drug.

When tetracyclines are used during tooth development, they may deposit in dental tissues, causing permanent discoloration (see section "Special precautions for use").

Ability to affect reaction speed when driving vehicles or operating machinery.

There are no data indicating a negative effect of the drug on the ability to drive vehicles or operate moving machinery.

Method of Administration and Dosage

Tetracycline should be taken 1 hour before or 2 hours after meals, as food products, particularly certain dairy products, interfere with absorption. Tablets should be taken with a full glass of water.

Dosage and duration of treatment are determined individually by a physician depending on the nature and course of the disease.

Treatment should be continued for an additional three days after the disappearance of clinical manifestations of the disease.

All infections caused by β-hemolytic streptococcus should be treated for at least 10 days.

Adults and children aged 12 years and older: The usual dose is 500 mg twice daily. In severe infections, the dose may be increased to 500 mg four times daily.

Maximum daily dose — 2 g.

For the treatment of brucellosis: 500 mg of tetracycline four times daily for three weeks, concomitantly with streptomycin 1 g intramuscularly twice daily during the first week and once daily during the second week.

For the treatment of syphilis: For patients allergic to penicillin, the following tetracycline doses are recommended:

• Early syphilis (duration less than one year) — 500 mg four times daily for 15 days;
• Syphilis of more than one year duration (except neurosyphilis) — 500 mg four times daily for 30 days.

For the treatment of moderate to severe acne: The recommended initial dose is 1 g daily, divided into two doses. As improvement occurs, the dose should be gradually reduced to maintenance levels (from 125 mg to 500 mg daily). In some patients, adequate remission of lesions may be maintained with alternate-day or intermittent therapy. Tetracycline therapy for acne does not replace other standard preventive and treatment measures for acne vulgaris. The safe duration of treatment that can be recommended has not been established (see sections "Special Warnings" and "Adverse Reactions").

Elderly patients: Administer the usual adult dose. Use with caution in patients with subclinical renal impairment, as this may lead to drug accumulation.

Renal impairment: In general, tetracyclines are contraindicated in renal impairment except when use of this class of drugs is considered absolutely necessary. The daily dose should be reduced by lowering the recommended individual doses and/or by increasing the intervals between doses.

To reduce the risk of esophageal irritation and ulceration, it is recommended to take adequate fluid with the capsule form of tetracycline (see section "Adverse Reactions").

Children: The drug is not recommended for children under 12 years of age.

Overdose.

Symptoms: Nausea, vomiting; when doses significantly exceeding the recommended ones are used — crystalluria, hematuria. Exacerbation of the described adverse effects, including hypersensitivity reactions, may occur.

Treatment: Symptomatic therapy. There is no specific antidote. Tetracycline is not dialyzable.

Adverse reactions.

Immune system: hypersensitivity reactions, including urticaria, angioneurotic edema (including face and tongue), anaphylaxis, pericarditis, bronchospasm; anaphylactoid reactions, including anaphylactoid purpura, exacerbation of systemic lupus erythematosus, fixed drug eruption, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Skin and subcutaneous tissue: pruritus, skin hyperemia, rashes, including maculopapular, erythematous, photosensitization reactions, bullous dermatoses, disturbances of pigmentation of skin and mucous membranes.

Blood and lymphatic system: hemolytic anemia, thrombocytopenia, neutropenia, eosinophilia, agranulocytosis, aplastic anemia, Moschowitz disease.

Endocrine system: with prolonged use of tetracyclines, microscopic areas of brown-black pigmentation may appear in thyroid tissue. Thyroid function remains unaffected.

Nervous system: bulging of the fontanelle in infants and benign intracranial hypertension in adolescents and adults, the first symptoms of which may include headache, dizziness, tinnitus/hearing disturbances, visual disturbances (including optic nerve edema, blurred vision, scotoma, diplopia, photophobia), nausea, vomiting, unsteady gait. Cases of temporary/irreversible vision loss have been reported.

Gastrointestinal system: anorexia, nausea, vomiting, dry mouth, discomfort/pain in the abdomen, dyspepsia (including heartburn/gastritis), dysphagia, diarrhea/constipation, intestinal dysbiosis, pancreatitis. Cases of esophagitis and formation of esophageal ulcers, gastric and duodenal ulcers have been reported in patients taking tetracycline capsules and tablets.

Hepatobiliary system: hepatotoxicity with transient elevation of liver transaminases, alkaline phosphatase and bilirubin in blood, impaired liver function; hepatitis, jaundice, fatty liver degeneration, liver failure. Initial symptoms of liver damage may include malaise, fever and/or right upper quadrant pain, stomach pain, nausea, vomiting, subicterus of the sclera.

Effects due to biological action: prolonged use of high doses of antibiotics, including tetracycline, may lead to superinfection, potentially resulting in candidiasis, glossitis with papillary hypertrophy, glossophytia, stomatitis, staphylococcal enterocolitis, CDAD, pseudomembranous colitis, itching in the anal area, inflammatory lesions of the anogenital region (due to candidiasis), vulvovaginitis, balanitis, proctitis.

Musculoskeletal system: increased muscle weakness in patients with myasthenia gravis.

Renal system: azotemia, hypercreatininemia, nephritis, acute renal failure, usually in patients with pre-existing renal impairment.

Other: sore throat, hoarseness, pharyngitis, hypovitaminosis, irreversible tooth discoloration (yellow-brown-gray), enamel hypoplasia in children, impaired bone tissue formation, slowed linear bone growth (in children).

Shelf life.

3 years. Do not use after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 capsules in a blister; 3 or 6 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

LLC "AKTIFARM".

Manufacturer's address and location of business activity.

11 Pryozerna St., Horenka, Buchanskyi district, Kyiv region, 08150, Ukraine.

Marketing Authorization Holder.

LLC "AKTIFARM".

Address of the Marketing Authorization Holder.

10 O. Myshuhy St., office 212, Kyiv, 02141, Ukraine.

INSTRUCTION

for medical use of the medicinal product

TETRAMAX

(TETRAMAX)

Composition:

Active ingredient: tetracycline hydrochloride;

1 capsule contains tetracycline hydrochloride 500 mg, calculated as 100% anhydrous substance;

Excipients: lactose monohydrate, magnesium stearate; hard gelatin capsule: gelatin, azorubine (E122), indigocarmine (E132), titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172).

Pharmaceutical form. Capsules.

Main physico-chemical properties: hard gelatin capsules of cylindrical shape with hemispherical ends; body — pink, cap — burgundy. The capsule contents are a powder ranging from yellow to yellow-brown; presence of agglomerate particles (a cluster of particles firmly adhering together) is acceptable.

Pharmacotherapeutic group. Antibacterials for systemic use. Tetracyclines. ATC code J01AA07.

Pharmacological Properties

Pharmacodynamics

Bacteriostatic antibiotic of the tetracycline group with a broad spectrum of activity. Inhibits protein synthesis by blocking the binding of aminoacyl-transfer RNA (tRNA) to the messenger RNA (mRNA)—ribosome complex. Active against Gram-positive (Staphylococcus spp., including penicillinase-producing strains; Streptococcus spp., including Streptococcus pneumoniae; Haemophilus influenzae, Listeria spp., Bacillus anthracis) and Gram-negative microorganisms (Neisseria gonorrhoeae, Bordetella pertussis, Escherichia coli, Enterobacter spp., Klebsiella spp., Salmonella spp., Shigella spp.), as well as Rickettsia spp., Chlamydia spp., Mycoplasma spp., Treponema spp., Borrelia spp., Vibrio cholerae, Chlamydophila psittaci, Francisella tularensis, Campylobacter, Bartonella. Resistant to the drug's action are: Pseudomonas aeruginosa, Proteus spp., Serratia spp., most strains of Bacteroides spp., fungi, and small viruses.

Pharmacokinetics

One hour after intravenous administration or rapid infusion of a single 500 mg dose of tetracycline hydrochloride, its plasma concentration reaches 4–5 mg/L. With repeated dosing at 12-hour intervals, some accumulation occurs, resulting in average plasma concentrations of tetracycline of 6.4 mg/L.

Following oral administration of 500 mg tetracycline hydrochloride, maximum plasma concentrations are achieved within 2 hours and average 3.0–4.3 mg/L after a single dose. After repeated oral doses of 500 mg in adults with normal liver function, steady-state plasma concentrations of tetracycline reach 1.5–4.3 mg/L. However, increasing the dose is not accompanied by a proportional increase in plasma concentration.

The bioavailability of tetracycline after oral administration in fasting adults is 75–80%.

In adults with normal renal function, the elimination half-life from plasma is 8–9 hours, although it may be significantly prolonged in patients with renal impairment, depending on the degree of kidney damage. Plasma protein binding ranges from 36% to 64%.

Tetracycline hydrochloride is only slightly absorbed after intramuscular injection, resulting in lower plasma concentrations compared to oral administration.

Intestinal absorption may be significantly reduced when taken simultaneously with certain foods or medicinal products. In particular, polyvalent cations such as iron, manganese, magnesium, and calcium can form non-absorbable chelate complexes with tetracycline.

Tetracycline is well distributed into tissues, particularly the liver, gallbladder, kidneys, bones, teeth, genital organs, and mucous membranes of the nasal sinuses. Effective concentrations are also achieved in various body fluids (pleural, pericardial, peritoneal, and synovial fluids). On the other hand, in cerebrospinal fluid, it is present only in low concentrations, amounting to only 10–30% of its plasma levels, even during inflammation of the meninges.

Tetracycline accumulates in the liver. It is excreted into the gastrointestinal tract via bile and is partially reabsorbed (enterohepatic circulation).

Approximately 30–50% of tetracycline is metabolized, while 30–70% is excreted unchanged in urine. It undergoes dialysis only to a minor extent, and peritoneal dialysis is ineffective.

Clinical characteristics.

Indications.

The medicinal product is indicated for infectious and inflammatory diseases caused by microorganisms sensitive to tetracycline hydrochloride, such as:

• Infections of the upper respiratory tract.
• Infections of the lower respiratory tract.
• Rickettsial diseases, including Rocky Mountain spotted fever, typhus group infections, and Q fever.
• Psittacosis.
• Trachoma.
• Granuloma inguinale.
• Relapsing fever borreliosis — as part of combination therapy.
• Bartonellosis.
• Tularemia.
• Cholera.
• Brucellosis.
• Campylobacteriosis — as part of combination therapy.
• Urinary tract infections.
• Other infections caused by susceptible gram-negative organisms.
• Severe forms of acne — as part of combination therapy.

When penicillin is contraindicated, tetracycline may be used as an alternative for the treatment of the following infections:

• Syphilis.
• Gonorrhea.

Contraindications.

Hypersensitivity to tetracycline hydrochloride and related antibiotics, local anesthetics (lidocaine, procaine); fungal infections, systemic lupus erythematosus. Pregnancy. Lactation. Patient age under 12 years. Liver and kidney diseases with pronounced functional insufficiency.

Cases of benign intracranial hypertension have been reported with concomitant use of tetracyclines and vitamin A or retinoids; therefore, their simultaneous administration is contraindicated.

Interaction with other medicinal products and other forms of interactions.

Iron salts, oral zinc and calcium preparations, bismuth (including bismuth subsalicylate), aluminum, magnesium, and other products containing these cations (including magnesium-containing laxatives, antacids, sucralfate), cholestyramine, colestipol, kaolin-pectin, sodium bicarbonate: formation of inactive chelates with tetracycline and reduced absorption of tetracycline. Combination with these agents should be avoided, as well as with quinapril (contains magnesium carbonate) and didanosine (contains calcium- and magnesium-containing excipients). If such combination is necessary, tetracycline should be administered at least 2 hours before or 4–6 hours after administration of these agents.

Strontium ranelate: possible reduction in tetracycline serum concentration. Concomitant use should be avoided. It is recommended to interrupt strontium ranelate treatment during tetracycline therapy.

Digoxin, lithium preparations: possible increase in their serum concentrations.

Ergotamine and methysergide: increased risk of ergotism.

Penicillins, cephalosporins, beta-lactam antibiotics: as a bacteriostatic antibiotic, tetracycline may interfere with the bactericidal activity of other antibiotics. Such combinations should be avoided.

Combination of tetracycline with oleandomycin and erythromycin is considered synergistic.

Oral anticoagulants, including warfarin, phenindione, antithrombotic agents: tetracyclines may enhance the effect of oral anticoagulants by inhibiting their hepatic metabolism, reduce plasma prothrombin levels, requiring careful monitoring of prothrombin time and, if necessary, reduction of anticoagulant dosage.

Atovaquone: decreased plasma concentration of atovaquone.

Methoxyflurane: possible nephrotoxic effects (including increased blood urea nitrogen and serum creatinine levels), acute renal failure, sometimes fatal.

Methotrexate: possible increase in its toxicity; such combination should be used with caution. Regular monitoring of methotrexate toxicity is required if concomitant administration is necessary.

Vitamin A and retinoids, such as acitretin, isotretinoin, and tretinoin (for acne treatment), when used concomitantly with tetracyclines, may cause benign intracranial hypertension; therefore, their simultaneous use is contraindicated. To prevent this complication during acne treatment with retinoids, an interval should be maintained after tetracycline therapy.

Hormonal contraceptives: reduced efficacy (unplanned pregnancy) and increased frequency of breakthrough bleeding when used with tetracyclines. Therefore, non-hormonal contraceptive methods are recommended during tetracycline treatment and for 7 days after completion of therapy.

Diuretics: such combination requires caution, as dehydration increases the risk of nephrotoxicity.

Antidiabetic agents (insulin, sulfonylureas, including glibenclamide, glipizide): enhanced hypoglycemic effect.

Chymotrypsin increases tetracycline concentration and prolongs its circulation in the blood.

Tetracycline should be administered with caution together with hepatotoxic agents.

Oral typhoid vaccine, BCG vaccine: antibacterial agents, including tetracyclines, may reduce the therapeutic efficacy of these vaccines. Vaccination should be avoided during antibiotic treatment.

Tetracycline absorption is impaired when administered with food, milk, or dairy products.

Special precautions for use.

Esophagitis. Cases of esophagitis and esophageal ulcers have been reported in patients taking encapsulated or tablet forms of tetracyclines. The drug should be taken with a sufficient amount of liquid and swallowed in an upright position (sitting or standing), well before bedtime. If symptoms such as dysphagia or substernal pain occur, the possibility of this complication should be considered and discontinuation of the drug should be evaluated. Tetracycline should be used with caution in patients with esophageal reflux.

Photosensitization. Cases of photosensitivity reactions with clinical manifestations of severe sunburn have been reported in patients taking tetracyclines. During treatment, patients should protect exposed skin areas from direct sunlight and artificial UV radiation. Patients should be informed about the possibility of such reactions and advised that treatment with tetracyclines should be discontinued immediately at the first signs of skin erythema.

Due to the potential development of photodermatoses (increased photosensitivity during use of tetracycline-class antibiotics), the drug should not be used when exposed to sunlight or UV radiation.

Microflora. Antibiotic use may lead to overgrowth of resistant microorganisms, including fungi such as Candida, and to the development of superinfection, which may require discontinuation of the antibiotic and appropriate interventions.

To prevent the development of candidiasis, concomitant use of antifungal agents and vitamins is recommended during tetracycline therapy.

Diarrhea, especially severe, persistent, and/or with blood, occurring during or after treatment (including several weeks after treatment) with tetracycline may be a symptom of Clostridium difficile-associated diarrhea (CDAD). The severity of CDAD may range from moderate diarrhea to life-threatening pseudomembranous colitis.

CDAD should be considered in all patients who develop severe diarrhea during or after antibiotic therapy.

Tooth development. Use of tetracyclines during tooth development (second and third trimesters of pregnancy, breastfeeding period, neonatal period, and childhood up to 12 years of age) may cause irreversible discoloration of teeth (yellow-brown-gray). This adverse reaction occurs more frequently with prolonged use but may also occur after repeated short courses of treatment. Cases of enamel hypoplasia have also been reported.

Venereal diseases. Tetracyclines may mask the symptoms of syphilis. When treating venereal diseases with suspected concurrent syphilis, appropriate diagnostic procedures should be performed. In all such cases, monthly serological tests should be conducted for at least 4 months.

Beta-hemolytic streptococci. For infections caused by group A beta-hemolytic streptococci, treatment should last for at least 10 days.

Myasthenia gravis. The drug should be used with caution in patients with myasthenia gravis due to the potential for developing weak neuromuscular blockade.

Systemic lupus erythematosus, porphyria. Tetracyclines may cause exacerbation of systemic lupus erythematosus. Rare cases of porphyria have been observed in patients receiving tetracyclines. Therefore, tetracyclines should not be used in patients with porphyria or systemic lupus erythematosus.

Renal function impairment. The use of tetracycline is generally contraindicated in renal insufficiency due to the risk of excessive accumulation and increased likelihood of adverse effects.

Antianabolic effect of tetracyclines may lead to elevated blood urea nitrogen levels. While this is not significant in patients with normal renal function, in patients with severely impaired renal function, high serum tetracycline levels may result in azotemia, hyperphosphatemia, and acidosis.

Hepatic function impairment. Tetracycline should be used with caution in patients with impaired liver function and in those receiving potentially hepatotoxic drugs. High doses of the drug should be avoided. High-dose tetracycline use has been associated with fatty infiltration of the liver and pancreatitis.

Tetracycline hydrochloride should be prescribed with caution in leukopenia.

Since tetracyclines reduce plasma prothrombin activity, patients on anticoagulant therapy may require a reduction in anticoagulant dosage.

During prolonged treatment, periodic blood tests, renal function tests, and liver function tests should be performed.

Tetracycline therapy should be conducted under medical supervision. The prescribed dosing regimen must be strictly followed throughout the treatment course, without missing doses and taken at regular intervals. If a dose is missed, it should be taken as soon as possible; however, if the next dose is nearly due, the missed dose should be skipped; doses should not be doubled. Tetracycline hydrochloride should not be taken simultaneously with milk or other dairy products, as this impairs its absorption.

If signs of hypersensitivity or adverse reactions occur, the drug should be discontinued; if necessary, another antibiotic (not from the tetracycline group) should be prescribed. To prevent possible complications, concomitant use of hepatoprotectors, choleretics, eubiotics, vitamins, and antifungal agents may be advisable.

Tetracycline is not the drug of choice for the treatment of any type of staphylococcal infection.

Prescribing the drug to adults in doses less than 800 mg per day is not advisable, as it may result not only in insufficient therapeutic effect but also in the development of tetracycline-resistant microbial strains.

The medicinal product contains lactose; therefore, if the patient has known sugar intolerance, consultation with a physician is required before taking the drug.

The medicinal product contains the azorubine dye (E122), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Tetracyclines cross the placenta and may have toxic effects on fetal tissues, particularly on skeletal development; therefore, the drug is contraindicated during pregnancy.

Tetracyclines are excreted in breast milk and are therefore contraindicated during breastfeeding.

All tetracyclines form stable calcium complexes in any calcifying tissue (skeletal system, tooth enamel, dentin). Reduced growth rate of the tibia has been observed in premature infants receiving oral tetracycline at a dose of 25 mg/kg every 6 hours. This adverse reaction was reversible upon discontinuation of the drug.

When tetracyclines are used during tooth development, they may deposit in dental tissues, causing permanent discoloration (see section "Special precautions for use").

Ability to influence reaction speed when driving vehicles or operating machinery.

There are no data on the negative impact of the medicinal product on the ability to drive vehicles or operate moving machinery.

Method of Administration and Dosage

Tetracycline should be taken 1 hour before or 2 hours after meals, as food products, particularly certain dairy products, interfere with its absorption. Tablets should be taken with a full glass of water.

Dosage and duration of treatment are determined individually by a physician depending on the nature and course of the disease.

Treatment should be continued for an additional three days after the disappearance of clinical symptoms of the disease.

All infections caused by β-hemolytic streptococcus should be treated for at least 10 days.

Adults and children aged 12 years and older: The usual dose is 500 mg twice daily. In severe infections, the dose may be increased to 500 mg four times daily.

Maximum daily dose — 2 g.

For the treatment of brucellosis: 500 mg of tetracycline four times daily for three weeks, concomitantly with streptomycin 1 g intramuscularly twice daily during the first week and once daily during the second week.

For the treatment of syphilis: For patients allergic to penicillin, the following tetracycline doses are recommended:

• early syphilis (duration less than one year) — 500 mg four times daily for 15 days;
• syphilis of more than one year duration (excluding neurosyphilis) — 500 mg four times daily for 30 days.

For the treatment of moderate to severe acne: The recommended initial dose is 1 g daily, divided into two doses. Upon improvement, the dose should be gradually reduced to maintenance levels (from 125 mg to 500 mg daily). In some patients, adequate remission of lesions may be maintained with alternate-day or intermittent therapy. Tetracycline therapy for acne does not replace other standard preventive and treatment measures for acne vulgaris. The safe duration of treatment that can be recommended has not been established (see sections "Special Warnings" and "Adverse Reactions").

Elderly patients: Administer the usual adult dose. Use with caution in patients with subclinical renal impairment, as this may lead to drug accumulation.

Renal impairment: Generally, tetracyclines are contraindicated in renal impairment except when use of this class of drugs is considered absolutely necessary. The daily dose should be reduced by lowering the recommended individual doses and/or by increasing the intervals between doses.

To reduce the risk of esophageal irritation and ulceration, it is recommended to take an adequate amount of fluid with the capsule form of tetracycline (see section "Adverse Reactions").

Children: The drug should not be administered to children under 12 years of age.

Overdose.

Symptoms: nausea, vomiting; when doses significantly exceeding the recommended are used — crystalluria, hematuria. Exacerbation of the described adverse effects, including hypersensitivity reactions, may occur.

Treatment: symptomatic therapy. There is no specific antidote. Tetracycline is not dialyzable.

Side effects.

Immune system: hypersensitivity reactions, including urticaria, angioedema (including of the face and tongue), anaphylaxis, pericarditis, bronchospasm; anaphylactoid reactions, including anaphylactoid purpura, exacerbation of systemic lupus erythematosus, fixed drug eruption, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Skin and subcutaneous tissue: pruritus, skin hyperemia, rashes (including maculopapular, erythematous), photosensitization reactions, bullous dermatoses, disturbances in pigmentation of the skin and mucous membranes.

Blood and lymphatic system: hemolytic anemia, thrombocytopenia, neutropenia, eosinophilia, agranulocytosis, aplastic anemia, Moschowitz disease.

Endocrine system: with prolonged use of tetracyclines, microscopic areas of brown-black pigmentation may appear in thyroid tissue. Thyroid function remains unaffected.

Nervous system: bulging of the fontanelle in infants and benign intracranial hypertension in adolescents and adults, the first symptoms of which may include headache, dizziness, tinnitus/hearing disturbances, visual disturbances (including optic nerve edema, blurred vision, scotoma, diplopia, photophobia), nausea, vomiting, unsteady gait. Cases of temporary/permanent vision loss have been reported.

Gastrointestinal system: anorexia, nausea, vomiting, dry mouth, abdominal discomfort/pain, dyspepsia (including heartburn/gastritis), dysphagia, diarrhea/constipation, intestinal dysbiosis, pancreatitis. Cases of esophagitis and formation of esophageal ulcers, gastric ulcers, and duodenal ulcers have been reported in patients taking tetracycline capsules and tablets.

Hepatobiliary system: hepatotoxicity with transient increases in blood levels of liver transaminases, alkaline phosphatase, and bilirubin, impaired liver function; hepatitis, jaundice, fatty liver degeneration, liver failure. Initial symptoms of liver involvement may include malaise, fever and/or right upper quadrant pain, epigastric pain, nausea, vomiting, subicterus of the sclera.

Effects due to biological activity: prolonged use of high doses of antibiotics, including tetracycline, may lead to superinfection, potentially resulting in candidiasis, glossitis with papillary hypertrophy, glossophytia, stomatitis, staphylococcal enterocolitis, CDAD, pseudomembranous colitis, anal itching, inflammatory lesions of the anogenital area (due to candidiasis), vulvovaginitis, balanitis, proctitis.

Musculoskeletal system: increased muscle weakness in patients with myasthenia gravis.

Renal and urinary system: azotemia, hypercreatininemia, nephritis, acute renal failure, usually in patients with pre-existing renal impairment.

Other: sore throat, hoarseness, pharyngitis, hypovitaminosis, irreversible tooth discoloration (yellow-brown-gray), enamel hypoplasia in children, impaired bone tissue formation, slowed linear bone growth (in children).

Shelf life.

3 years. Do not use after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 capsules in a blister; 3 or 6 blisters per carton.

Prescription category.

Prescription only.

Manufacturer.

JSC "VITAMINY".

Manufacturer's address and location of operations.

31 Uspenska St., Uman, Cherkasy region, 20300, Ukraine.

Marketing Authorization Holder.

LLC "AKTIFARM".

Address of the Marketing Authorization Holder.

10A Myshuhy St., office 212, Kyiv, 02141, Ukraine