Doxycycline-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Doxycycline-Teva (Doxycycline-Teva)

Composition:

Active substance: doxycycline monohydrate;

One tablet contains 100 mg of doxycycline in the form of doxycycline monohydrate;

Excipients: microcrystalline cellulose, sodium starch glycolate (type A), talc, magnesium stearate, colloidal anhydrous silicon dioxide, purified water.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: greenish-yellow tablets with uniform or non-uniform discoloration, "speckled", round, biconvex tablets with a score line on one side.

Pharmacotherapeutic group. Antibacterial agent for systemic use. ATC code J01A A02.

Pharmacological Properties.

Pharmacodynamics.

Doxycycline exerts a bacteriostatic effect; its antimicrobial action is achieved by inhibition of protein synthesis. The medicinal product is effective against a broad spectrum of Gram-positive and Gram-negative bacteria and certain other microorganisms.

Pharmacokinetics.

Absorption. After oral administration, doxycycline is almost completely absorbed in the upper part of the small intestine (>90% of the dose). Significant plasma concentrations are achieved within 30 minutes, and maximum plasma concentration is reached within 1–2 hours. After a single 200 mg dose, peak plasma concentrations ranged from 3 to 5.3 mg/L. When administered under therapeutic conditions (200 mg on the first day of treatment and 100 mg on subsequent days), steady-state concentrations are rapidly achieved and are nearly as high as those after a single 200 mg dose.

The elimination half-life in plasma in healthy individuals is approximately 16±6 hours; it may be slightly prolonged in patients with renal impairment and significantly prolonged in patients with hepatic disease. Protein binding of doxycycline ranges from 80% to 90%.

Distribution. The drug rapidly distributes throughout the body, penetrating the central nervous system only in relatively small amounts, even through inflamed meninges. High concentrations in the gallbladder and good tissue penetration are achieved in the liver, kidneys, lungs, spleen, bones, and genital organs. The apparent volume of distribution of doxycycline is approximately 0.75 L/kg.

Biological transformation. Doxycycline is metabolized in the human body only to a minor extent (≤10% of the dose).

Elimination. Elimination occurs primarily in microbiologically active form via the intestine (through transintestinal secretion or via the gallbladder), with 30–55% of the dose excreted by the kidneys. Approximately 41% (range: 22–60%) of the administered dose is recovered in urine within 24 hours. Due to these pharmacokinetic characteristics, the elimination half-life of doxycycline is only slightly prolonged in patients with significant renal impairment.

Clinical characteristics.

Indications.

For the treatment of infections caused by susceptible strains of gram-positive and gram-negative microorganisms and certain other microorganisms, namely:

Respiratory tract infections: pneumonia and other lower respiratory tract infections caused by susceptible strains of Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae, etc. Pneumonia caused by Mycoplasma pneumoniae. Chronic bronchitis, sinusitis.

Urinary tract infections: infections caused by susceptible strains of Klebsiella, Enterobacter, as well as Escherichia coli, Streptococcus faecalis, etc.

Sexually transmitted diseases: infections caused by Chlamydia trachomatis, including uncomplicated urethral and endocervical infections and rectal infections. Nongonococcal urethritis caused by Ureaplasma urealyticum (T-mycoplasma). Chancroid, granuloma inguinale, lymphogranuloma venereum. Doxycycline is an alternative agent for the treatment of gonorrhea and syphilis.

Skin infections: acne, when antibiotic therapy is indicated.

Since doxycycline belongs to the tetracycline class of antibiotics, it may be used in infections caused by microorganisms susceptible to tetracyclines, namely:

Ophthalmic infections: infections caused by susceptible bacteria such as gonococci, staphylococci, and Haemophilus influenzae. Trachoma infection is not always eliminated, as confirmed by immunofluorescence testing. For the treatment of paratrachoma, doxycycline may be used as monotherapy or in combination with other medicinal products.

Rickettsial infections: Rocky Mountain spotted fever, typhus group, Q fever, endocarditis caused by Coxiella, tick-borne fever.

Other infections: psittacosis, brucellosis (when used in combination with streptomycin), cholera, bubonic plague, epidemic relapsing fever; tick-borne relapsing fever; tularemia, melioidosis, chloroquine-resistant tropical malaria, and acute intestinal amoebiasis (when used in combination with an amebicide).

Doxycycline is an alternative agent for the treatment of leptospirosis, gas gangrene, and tetanus.

Doxycycline is indicated for prophylaxis of the following conditions: Japanese river fever (Japanese encephalitis), traveler’s diarrhea (caused by enterotoxigenic Escherichia coli), leptospirosis, malaria. Malaria prophylaxis should be conducted in accordance with current guidelines due to the potential for resistance development.

Contraindications.

• Hypersensitivity to doxycycline or to other tetracyclines or to any excipient of the medicinal product;
• severe impairment of liver function;
• pregnancy or breastfeeding (see also section "Use during pregnancy or breastfeeding");
• children under 12 years of age (see also section "Children").

Interaction with other medicinal products and other forms of interaction.

Effect of other drugs on doxycycline

The absorption of doxycycline from the gastrointestinal tract may be reduced when administered concomitantly with antacids containing aluminum, calcium, or magnesium, or when taken with other products or foods containing these cations (e.g., milk, dairy products, and fruit juices containing calcium), or with oral zinc, iron salts, bismuth preparations, activated charcoal, colestipol, or cholestyramine. Administration of doxycycline together with such agents should be spaced as far apart in time as possible.

Rifampicin, barbiturate inducers, anticonvulsant drugs such as carbamazepine, phenytoin, primidone, and chronic alcohol consumption may accelerate the breakdown of doxycycline in the liver by inducing hepatic enzymes, resulting in subtherapeutic blood concentrations of doxycycline when standard doses are used. In such cases, increasing the daily dose of doxycycline should be considered.

Effect of doxycycline on other drugs

Doxycycline may enhance the hypoglycemic effect of sulfonylurea derivatives (oral antidiabetic agents). Blood glucose levels should be monitored during concomitant use, and doses of these agents may need to be reduced if necessary.

There have been reports of prolonged prothrombin time in patients receiving anticoagulants (e.g., warfarin, phenprocoumon) and doxycycline. Tetracyclines reduce plasma prothrombin activity; therefore, a reduction in anticoagulant dosage may be required.

Doxycycline may increase plasma concentrations of cyclosporine A, thereby increasing the toxic effects of the immunosuppressant. Concomitant use of these drugs should be closely monitored.

Concomitant use with methotrexate may lead to increased toxicity of the latter.

Other interactions

Concomitant use of methoxyflurane or other potentially nephrotoxic agents with doxycycline may result in potentially fatal nephrotoxic adverse reactions.

Doxycycline should be avoided for some time before, during, and after isotretinoin (or other retinoid) treatment for acne, as both agents may in some cases cause reversible intracranial hypertension (Pseudotumor cerebri) (see section "Adverse reactions").

Concomitant therapy with digoxin or digoxin derivatives may increase the risk of elevated digoxin plasma concentrations, potentially leading to digoxin toxicity (nausea, vomiting, dizziness, fatigue, cardiac arrhythmias).

Bacteriostatic agents may antagonize the effects of bactericidal agents; therefore, concomitant use of doxycycline and beta-lactam antibiotics should be avoided, as this may reduce antibacterial efficacy.

Concomitant use of theophylline and doxycycline increases the risk of gastrointestinal adverse effects.

There have been several reports of pregnancy and breakthrough bleeding with concomitant use of tetracycline antibiotics and oral contraceptives.

Tetracyclines may inhibit the hepatic metabolism of ergot alkaloids (individual cases of ergotism are possible).

Inaccurate laboratory test results

Glucose tests in urine may yield false-positive results when using the copper sulfate method (Benedict's test). Glucose tests in urine using glucose oxidase reagents may yield false-negative results. With fluorometric tests, false elevation of urinary catecholamine levels may occur.

Administration of tetracyclines may lead to inaccurate laboratory test results for protein and urobilinogen in urine.

Special precautions for use.

Photosensitivity. Cases of photosensitivity with clinical manifestations of severe sunburn reactions may occur in patients taking tetracycline-class drugs following exposure to direct sunlight or ultraviolet radiation. Patients should be informed about the risk of developing such reactions when exposed to direct sunlight or ultraviolet radiation during treatment with tetracycline-class drugs and about the necessity to discontinue treatment at the first signs of erythema. Cases of photo-onycholysis have been reported in patients taking doxycycline (see section "Adverse reactions"). During doxycycline therapy, exposure to natural sunlight or use of tanning beds should be avoided.

Patients with hepatic impairment. Doxycycline should be used with caution in patients with impaired liver function and in those concurrently receiving potentially hepatotoxic drugs. Rare cases of abnormal liver function tests have been reported during both oral and parenteral administration of tetracyclines, including doxycycline. With prolonged use (i.e., longer than 21 days), regular blood tests and monitoring of liver and kidney function are required. With prolonged treatment, potential deficiency of B-group vitamins should be considered.

Patients with renal impairment. In patients with normal renal function, renal excretion of doxycycline is approximately 40% over 72 hours. This value may decrease to 1–5% over 72 hours in patients with severe renal impairment (creatinine clearance below 10 mL/min). Studies have shown no significant difference in the elimination half-life of doxycycline in serum between patients with normal renal function and those with renal failure. Hemodialysis does not affect the elimination half-life of doxycycline from serum.

The anti-anabolic effect of tetracyclines may increase blood urea levels. Studies have not shown that this anti-anabolic effect occurs when doxycycline is administered to patients with renal impairment.

Tetracyclines may cause nephrotoxic damage or exacerbate existing kidney injury (characterized by elevated serum creatinine and urea levels).

Serious skin reactions. Serious skin reactions such as exfoliative dermatitis, erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving doxycycline (see section "Adverse reactions"). If serious skin reactions occur, doxycycline should be discontinued immediately and appropriate therapy initiated.

Overgrowth of microflora. Doxycycline treatment may lead to overgrowth of microorganisms on the skin or mucous membranes (e.g., genital tract, oral mucosa, or gastrointestinal tract), due to selection of resistant organisms (e.g., Candida) (see section "Adverse reactions"). Resulting infections require treatment.

Cases of pseudomembranous colitis have been reported in patients treated with antibacterial agents, including doxycycline. The severity of the disease ranged from mild to life-threatening. It is important to consider this diagnosis in patients who develop diarrhea following antibacterial therapy.

Diarrhea associated with Clostridium difficile (CDAD) has been reported with the use of antibacterial agents, including doxycycline, with severity ranging from mild to fatal colitis. Antibacterial agents alter normal gut flora, leading to overgrowth of C. difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD.

Toxin-producing strains of C. difficile may increase morbidity and mortality, as such infections are resistant to antibacterial therapy and may require colectomy. This diagnosis should be considered in patients presenting with diarrhea following antibacterial therapy. If CDAD is confirmed, doxycycline should be discontinued immediately and appropriate treatment initiated. The use of peristalsis inhibitors is contraindicated. A careful medical history is essential, as CDAD has been reported even more than 2 months after completion of antibacterial therapy.

Esophagitis. Esophagitis and esophageal ulceration have been reported with the use of tetracyclines, including doxycycline, in tablet and capsule forms. Most affected patients had taken the drug immediately before bedtime or with insufficient fluid.

Porphyria. Rare cases of porphyria exacerbation have been reported in patients receiving tetracyclines.

Sexually transmitted diseases. During treatment of sexually transmitted infections, appropriate diagnostic tests, including dark-field microscopy, should be performed if coexisting syphilis is suspected. In such cases, serological testing should be performed monthly for at least 4 months.

In some patients with spirochetal infections, a Jarisch–Herxheimer reaction may occur shortly after initiation of doxycycline therapy. In such cases, patients should be informed that this reaction is a consequence of antibacterial therapy for spirochetal infections and usually resolves spontaneously.

Infections caused by β-hemolytic streptococci. For infections caused by group A β-hemolytic streptococci, treatment should last at least 10 days.

Myasthenia gravis. Due to the potential for weak neuromuscular blockade, doxycycline should be used with caution in patients with myasthenia gravis.

Systemic lupus erythematosus. The use of tetracyclines may exacerbate systemic lupus erythematosus.

Methoxyflurane. Methoxyflurane should be used with caution when administered concomitantly with tetracyclines (see section "Interaction with other medicinal products and other forms of interaction").

Benign intracranial hypertension. Bulging of the fontanelle has been reported in infants receiving tetracycline therapy. Benign intracranial hypertension (pseudotumor cerebri) has been associated with the use of tetracyclines (including doxycycline). Benign intracranial hypertension (pseudotumor cerebri) is usually transient, but cases of irreversible vision loss due to benign intracranial hypertension (pseudotumor cerebri) have been reported with tetracycline (including doxycycline) use. If visual disturbances occur during treatment, urgent ophthalmological evaluation is required. Since intracranial pressure may remain elevated for several weeks after discontinuation of the drug, patients should be monitored until their condition stabilizes. Concomitant use of isotretinoin, or other systemic retinoids, with doxycycline should be avoided, as isotretinoin is also known to cause benign intracranial hypertension (pseudotumor cerebri) (see section "Interaction with other medicinal products and other forms of interaction").

Children. The use of tetracycline-class drugs during tooth development (second half of pregnancy, infants, and children under 8 years of age) may cause permanent tooth discoloration (yellow–gray–brown). This adverse reaction is more common with prolonged treatment, but has also been observed after repeated short courses. Enamel hypoplasia has also been reported.

Use during pregnancy or breastfeeding.

Pregnancy

The medicinal product is contraindicated during pregnancy. The risks associated with tetracycline use during pregnancy are primarily due to their effects on the development of teeth, bones, and skeleton (see section "Special precautions for use" regarding use during tooth development).

During pregnancy, there is an increased risk of developing liver damage with tetracycline use.

Breastfeeding

Tetracyclines are excreted in breast milk; therefore, the use of this drug is contraindicated during breastfeeding (see section " Special precautions for use " regarding use during tooth development).

Ability to affect reaction speed when driving or operating machinery.

The effect of doxycycline on the ability to drive or operate machinery has not been studied. If adverse reactions such as arterial hypotension, tinnitus, blurred vision, scotoma, diplopia, or prolonged vision loss occur, patients should refrain from driving or operating machinery.

Method of Administration and Dosage.

The medication should be taken regularly in the morning with breakfast or another meal, swallowed with a large amount of liquid (not milk or dairy products), while remaining in an upright position. It is not recommended to lie down immediately after taking the medication. Administration after or during a meal helps reduce the frequency of gastrointestinal adverse events and only slightly affects the rate of absorption.

Adults. The usual dose of doxycycline for the treatment of acute infections in adults is 200 mg on the first day of treatment (as a single dose or 100 mg every 12 hours), followed by 100 mg daily in subsequent days. For the treatment of severe infections, the drug should be administered at a dose of 200 mg daily throughout the entire treatment period.

Exceeding the recommended dose may increase the frequency of adverse reactions. Therapy should continue for 24–48 hours after the disappearance of disease symptoms and fever.

In streptococcal infections, the drug should be administered for 10 days to prevent the development of rheumatic fever or glomerulonephritis.

Children. For children aged 12 years and older with body weight below 45 kg, the recommended dose is 4.4 mg/kg body weight (on the first day of treatment, the recommended dose may be administered as a single dose or in two divided doses); in subsequent days, the dose is 2.2 mg/kg body weight (as a single or divided dose). In more severe infections, the dose may be increased up to 4.4 mg/kg body weight.

Children with body weight above 45 kg should receive the standard adult dose.

Treatment of Specific Infections.

Acne: the recommended dose is 50 mg daily with food (including liquid) for 6–12 weeks.

Sexually transmitted diseases: for the treatment of uncomplicated gonococcal infections (excluding anorectal infections in males), uncomplicated urethral and endocervical infections, and rectal infections caused by Chlamydia trachomatis, and non-gonococcal urethritis caused by Ureaplasma urealyticum, the recommended dose is 100 mg twice daily for 7 days.

For the treatment of acute epididymo-orchitis caused by Chlamydia trachomatis or Neisseria gonorrhoeae, the drug should be administered at 100 mg twice daily for 10 days.

For the treatment of primary and secondary syphilis, the recommended dose for patients without confirmed pregnancy and with penicillin allergy is 200 mg orally twice daily for 2 weeks (as an alternative to penicillin therapy).

Epidemic relapsing fever, tick-borne relapsing fever: the recommended dose is 100–200 mg as a single dose, depending on the severity of the disease.

Chloroquine-resistant tropical malaria: the recommended dose is 200 mg daily for at least 7 days due to the potentially severe course of the infection.

As adjunctive therapy to doxycycline, a fast-acting schizonticide (e.g., quinine) should always be used, with dosage varying case by case, due to the potentially severe course of the infection.

Malaria prophylaxis: the recommended dose for adults is 100 mg daily. For children aged 12 years and older, the recommended dose is 2 mg/kg daily up to a total dose of 100 mg daily. Prophylaxis may be initiated 1–2 days before travel to a malaria-endemic region. Prophylactic use of the drug should continue daily during the stay in the malaria-endemic region and for 4 weeks after leaving the region. Current guidelines for malaria treatment should also be considered.

Prophylaxis of Japanese encephalitis: the recommended dose is 200 mg as a single dose.

Traveler’s diarrhea prophylaxis in adults: the recommended dose is 200 mg on the first day of travel (administered as a single 200 mg dose or 100 mg every 12 hours), followed by 100 mg daily on subsequent travel days. Information on use beyond 21 days for prophylaxis is lacking.

Leptospirosis prophylaxis: the recommended dose is 200 mg once weekly throughout the stay in a leptospirosis-endemic region and 200 mg at the end of the trip. Information on use beyond 21 days for prophylaxis is lacking.

Use in elderly patients: the drug may be used at standard doses without special precautions. Dose adjustment is not required in renal impairment.

Use in patients with renal impairment: administration of the drug at recommended doses does not lead to antibiotic accumulation in this patient population (see section "Special Warnings").

Use in patients with hepatic impairment: see section "Special Warnings".

Children.

The medication is contraindicated for use in children under 12 years of age.

Like other tetracyclines, Doxycycline-TEVA forms stable calcium complexes in any tissue undergoing calcification. Slowed growth of the tibia has been observed in premature infants receiving tetracyclines orally at a dose of 25 mg/kg every 6 hours. This adverse reaction is reversible upon discontinuation of the drug.

Overdose.

Doxycycline is not acutely toxic when several therapeutic doses are taken orally at once. Acute intoxications caused by doxycycline have not been described in the literature. Overdose may manifest as parenchymal liver and kidney damage or pancreatitis.

In case of overdose, administration of the drug should be immediately discontinued, gastric lavage should be performed, and symptomatic therapy initiated. In cases of oral doxycycline overdose, antacids, magnesium or calcium salts may be used to bind the unabsorbed portion of the drug, as tetracycline can form non-absorbable chelate complexes with these substances. Dialysis has almost no effect on the elimination half-life of the drug from blood serum and is therefore ineffective in overdose.

Adverse Reactions

The following adverse reactions have been observed in patients receiving tetracyclines, including doxycycline. The reactions are categorized by frequency as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

Infections and infestations

Rare: Candida colonization of the skin or mucous membranes (including genital tract, oral mucosa, or intestine), with symptoms such as inflammation of the oral and nasopharyngeal mucosa (glossitis, stomatitis), acute inflammation of the external female genital organs and vagina (vulvovaginitis), proctitis, anal pruritus.

Blood and lymphatic system disorders

Uncommon: coagulation disorders.

Rare: leukocytosis, thrombocytopenia, hemolytic anemia, neutropenia, eosinophilia, lymphopenia, lymphadenopathy, presence of atypical lymphocytes, and toxic granulation of granulocytes.

Immune system disorders

Common: anaphylactic reactions (including hypersensitivity, Henoch-Schönlein purpura, hypotension, pericarditis, angioneurotic edema, exacerbation of systemic lupus erythematosus, asthma, dyspnea, serum sickness, peripheral edema, tachycardia, urticaria).

Rare: anaphylactic shock, drug reaction with eosinophilia and systemic symptoms (DRESS).

Frequency not known: Jarisch-Herxheimer reaction (see section "Special precautions").

Metabolism and nutrition disorders

Rare: anorexia, porphyria.

Psychiatric and nervous system disorders

Common: headache.

Rare: agitation, anxiety; paresthesia; benign intracranial hypertension (Pseudotumor cerebri), with possible symptoms including headache, nausea, vomiting, visual disturbances (blurred vision, scotoma, diplopia), or vision loss due to optic disc swelling (cases of irreversible vision loss have been reported); bulging fontanelle; disturbances or loss of smell and taste sensation, sometimes partially irreversible.

Very rare: seizures.

Eye disorders

Very rare: transient myopia.

Ear and labyrinth disorders

Rare: tinnitus.

Vascular disorders

Rare: flushing.

Gastrointestinal disorders

Common: nausea, vomiting, flatulence, steatorrhea.

Uncommon: dyspepsia (heartburn/gastritis), inflammation of the oral and nasopharyngeal mucosa, dysphonia, black "hairy" tongue, irreversible tooth discoloration with enamel damage when used during tooth development.

Rare: pancreatitis, pseudomembranous colitis (diarrhea caused by C. difficile), esophageal ulcers, esophagitis, enterocolitis, abdominal pain, diarrhea, dysphagia, glossitis. General symptoms of esophagitis and esophageal ulcers include odynophagia, chest pain, and dysphagia.

Frequency not known: tooth discoloration (reversible discoloration of the surface of permanent teeth has been reported with doxycycline use).

Hepatobiliary disorders

Rare: liver failure, hepatitis, impaired liver function, jaundice, hepatotoxicity with transient elevation of liver function tests.

Skin and subcutaneous tissue disorders

Very common: photosensitivity reactions with erythema, skin swelling, and blistering.

Common: skin rashes, including maculopapular and erythematous rashes.

Rare: skin hyperpigmentation (with prolonged doxycycline use), severe skin reactions with systemic involvement that may be life-threatening (e.g., erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis), nail detachment and nail discoloration.

Musculoskeletal and connective tissue disorders

Uncommon: reversible inhibition of bone growth when used during pregnancy and in children under 8 years of age.

Rare: myalgia, arthralgia.

Renal and urinary disorders

Uncommon: hematuria.

Rare: increased blood urea nitrogen levels.

Very rare: kidney damage such as interstitial nephritis, acute renal failure, anuria.

Other disorders

Frequency not known: microscopic brown-black pigmentation of thyroid tissue has been observed after prolonged treatment (without impairment of thyroid function tests).

Shelf life. 5 years.

Storage conditions. Store at temperatures not exceeding 30°C, in a place inaccessible to children.

Packaging. 10 tablets in a blister; 1 blister per carton.

Prescription category. Prescription only.

Manufacturer. Merckle GmbH, Germany.

Manufacturer's address.
Ludwig-Merkle-Straße 3, 89143 Blaubeuren, Germany.