Doxycycline-darnitsa

INSTRUCTIONS for Medical Use of the Medicinal Product DOXYCYCLINE-DARNITSA (DOXYCYCLINE-DARNITSA)

Composition:

Active substance: doxycycline;

1 capsule contains doxycycline hyclate (calculated as doxycycline) 100 mg;

Excipients: lactose monohydrate, potato starch, calcium stearate.

Pharmaceutical form. Capsules.

Main physicochemical properties: hard capsules with yellow cap and body containing a yellowish powder with greenish tint and white specks.

Pharmacotherapeutic group. Antibacterials for systemic use. Tetracyclines. Doxycycline. ATC code J01AA02.

Pharmacological properties.

Pharmacodynamics.

Doxycycline is a broad-spectrum semisynthetic antibiotic of the tetracycline group. It exerts a bacteriostatic effect by inhibiting microbial protein synthesis through blocking the binding of aminoacyl-transfer RNA (tRNA) to the "messenger RNA (mRNA)–ribosome" complex.

Doxycycline is active against Gram-positive bacteria: aerobic cocci – Staphylococcus spp. (including penicillinase-producing strains), Streptococcus spp. (including Streptococcus pneumoniae); aerobic spore-forming bacteria – Bacillus anthracis; aerobic non-spore-forming bacteria – Clostridium spp.

It is also active against Gram-negative bacteria: aerobic cocci – Neisseria gonorrhoeae; aerobic bacteria – Escherichia coli, Shigella spp., Salmonella spp., Enterobacter spp., Klebsiella spp., Bordetella pertussis, as well as Rickettsia spp., Treponema spp., Mycoplasma spp., Chlamydia spp.

Resistant to doxycycline are: Pseudomonas aeruginosa, Proteus spp., Serratia spp., and most strains of Bacteroides fragilis.

Pharmacokinetics.

The drug is rapidly absorbed from the gastrointestinal tract, practically independent of food intake. It binds to plasma proteins by 80–90%. Maximum plasma concentration is reached within 2 hours after administration. Depending on the dose, therapeutic concentrations of doxycycline in the blood are maintained for 18–24 hours. The drug rapidly distributes into most body fluids, including bile, paranasal sinus secretions, pleural, synovial, and ascitic fluids. Concentrations in cerebrospinal fluid vary and, after parenteral administration, may reach 10–25% of serum concentrations. It is slowly eliminated from the body. The elimination half-life of the drug is 12–22 hours. A significant portion of doxycycline is excreted unchanged in feces; approximately 40% is excreted in urine.

Clinical characteristics.

Indications.

Treatment of infections caused by susceptible strains of gram-positive and gram-negative microorganisms, as well as 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; pneumonia caused by Mycoplasma pneumoniae; chronic bronchitis, sinusitis;
• Urinary tract infections: infections caused by susceptible strains of the genus Klebsiella, Enterobacter, as well as Escherichia coli, Streptococcus faecalis;
• Sexually transmitted infections: 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; the medicinal product is an alternative for the treatment of gonorrhea and syphilis;
• Skin infections: acne, when antibiotic therapy is required.

Treatment of infections caused by microorganisms sensitive to tetracyclines, namely:

• Ophthalmological infections: infections caused by sensitive bacteria such as gonococci, staphylococci, and Haemophilus influenzae. Infection causing trachoma is not always eliminated, as confirmed by immunofluorescence testing. For the treatment of paratrachoma, the medicinal product may be used as monotherapy or in combination with other medicinal products;
• Rickettsial infections: spotted fever group, Rocky Mountain spotted fever, Q fever, tick-borne fever, endocarditis caused by Coxiella;
• Other infections: ornithosis, 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 amoebicide).

Prophylaxis of the following conditions: 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 development of resistance.

Alternative treatment: leptospirosis, gas gangrene, tetanus.

Contraindications.

Hypersensitivity to tetracyclines or to any other components of the medicinal product; porphyria; severe hepatic insufficiency; leukopenia.

Interaction with other medicinal products and other types of interactions.

Concomitant use of the medicinal product with other medicinal products may result in:

With antacids (aluminum-, calcium-, magnesium-containing), kaolin, magnesium-containing laxatives, sodium bicarbonate, iron and zinc preparations, sucralfate, cholestyramine, colestipol – reduced absorption of doxycycline;

With barbiturates, carbamazepine, primidone, rifampicin, phenytoin – decreased plasma concentration and shortened elimination half-life (T1/2) of doxycycline (induction of monooxygenases and accelerated biotransformation), which may lead to reduced antibacterial effect;

With antithrombotic agents, indirect anticoagulants – potentiation of their effect; dose reduction of anticoagulants may be necessary;

With cyclosporine – increased plasma concentration of cyclosporine; this combination should be used under close monitoring;

With methoxyflurane – lethal nephrotoxic effect;

With retinoids – increased risk of intracranial hypertension; this combination should not be used;

With methotrexate – increased toxicity of methotrexate; this combination should be used with caution;

With hormonal contraceptives – reduced efficacy and increased frequency of breakthrough bleeding with estrogen-containing oral contraceptives;

With penicillins – reduced efficacy of penicillins;

With oral typhoid vaccines – reduced efficacy of vaccines; this combination should not be used.

Concomitant use of isotretinoin or other systemic retinoids and doxycycline should be avoided. Use of each of these agents alone has been associated with the development of benign intracranial hypertension (pseudotumor cerebri).

Special precautions for use.

To reduce gastric irritation, the medicinal product should be taken during meals with a sufficient amount of water.

During prolonged use of the medicinal product, regular monitoring of peripheral blood composition, liver function tests, and serum urea levels should be performed.

When treating infections caused by group A β-hemolytic streptococci, the duration of treatment should be at least 10 days.

When treating sexually transmitted infections with suspected concomitant syphilis, appropriate diagnostic procedures including dark-field microscopy and other tests should be applied. In such cases, monthly serological tests should be conducted for at least 4 months.

The medicinal product should be used with caution in patients with impaired liver function or in individuals receiving potentially hepatotoxic medicinal products. Cases of liver function impairment associated with oral or parenteral administration of tetracyclines, including doxycycline, have been reported very rarely.

The medicinal product should be used with caution in patients with myasthenia gravis, as tetracycline-class medicinal products, including doxycycline, may cause mild neuromuscular blockade.

Renal excretion of doxycycline in patients with normal renal function is approximately 40% within 72 hours. This range may decrease to 1–5% within 72 hours in individuals with severe renal impairment (creatinine clearance below 10 mL/min). Studies have not revealed a significant difference in the serum half-life of doxycycline between individuals with normal and impaired renal function. Hemodialysis does not affect the serum half-life of the medicinal product.

The anti-anabolic effect of tetracyclines may lead to increased blood urea levels. However, this anti-anabolic effect has not been observed with doxycycline use in patients with impaired renal function.

Photosensitivity reactions have been reported in some individuals taking tetracyclines, including doxycycline. During treatment with doxycycline and for 4–5 days after its discontinuation, exposed areas of skin should be protected from direct sunlight and artificial UV radiation. Treatment with tetracyclines, including doxycycline, should be discontinued immediately at the first signs of skin erythema.

Antibacterial medicinal products may lead to overgrowth of non-susceptible microorganisms, including Candida species. To prevent the development of candidiasis, antifungal medicinal products are recommended to be used concomitantly with doxycycline.

Antibacterial treatment alters the normal flora of the large intestine, leading to overgrowth of non-susceptible microorganisms, including Clostridium difficile. Cases of Clostridium difficile-associated diarrhea have been reported with the use of nearly all antibacterial medicinal products. Diarrhea may range from mild to life-threatening. Patients receiving antibacterial medicinal products should be closely monitored, as Clostridium difficile-associated diarrhea may occur up to two months after antibacterial treatment.

Pseudomembranous colitis has been reported in some individuals receiving antibacterial medicinal products, including doxycycline. The severity of this complication ranges from mild to life-threatening. This diagnosis should be considered in patients presenting with diarrhea following antibacterial treatment.

Esophagitis and esophageal ulcers have been reported in some individuals taking encapsulated or tablet forms of tetracycline-class medicinal products, including doxycycline. Most of these patients had taken the medicinal product immediately before bedtime or with insufficient fluid.

Mild intracranial hypertension and bulging of the fontanelle have been observed in newborns receiving the medicinal product at the maximum therapeutic dose. These complications resolve rapidly after discontinuation of the medicinal product.

In biopsies of the thyroid gland from patients who have received long-term doxycycline treatment, dark-brown discoloration of the tissue in microscopic preparations may occur.

The use of tetracyclines may exacerbate the course of systemic lupus erythematosus.

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. If serious skin reactions occur, doxycycline should be discontinued immediately and appropriate therapy initiated.

Cases of photo-onycholysis have been reported in patients taking doxycycline.

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. Ophthalmological examination should be performed urgently if visual disturbances occur during treatment. 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).

During fluorescent testing, false elevation of urinary catecholamine levels may be observed.

Alcoholic beverages should not be consumed during treatment.

The medicinal product contains lactose; therefore, it should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

The medicinal product is contraindicated during pregnancy because the use of tetracyclines during tooth development (during pregnancy) may cause permanent discoloration of teeth (yellow-brown-gray). This adverse reaction occurs more frequently with prolonged use but may also occur with repeated short courses of treatment. Hypoplasia of the enamel has also been reported.

The medicinal product is contraindicated during breastfeeding because tetracyclines are excreted in breast milk.

Ability to affect reaction speed when driving or operating machinery.

Until the individual patient's response to the medicinal product is known, driving or operating machinery should be avoided, as visual disturbances, dizziness, arterial hypertension, tinnitus, blurred vision, scotoma, diplopia, and prolonged vision loss may occur during treatment with doxycycline.

Method of Administration and Dosage

The medicinal product should be taken orally during or after a meal (it may be taken with milk or kefir).

Adults and children aged 12 years and older with body weight above 45 kg.

On the first day of treatment for acute infections, the daily dose is 200 mg as a single dose or 100 mg every 12 hours; on subsequent days – 100 mg. For treatment of severe infections, the medicinal product should be administered at a dose of 200 mg per day throughout the entire treatment period.

The duration of treatment is determined individually by a physician, continuing therapy for at least 24–48 hours after the disappearance of symptoms and normalization of body temperature.

Children aged 12 years with body weight up to 45 kg.

On the first day of treatment, the daily dose of the medicinal product is 4.4 mg/kg body weight (in 1 or 2 doses); on subsequent days – 2.2 mg/kg body weight (in 1 or 2 doses). For treatment of severe infections, a dose of 4.4 mg/kg body weight may be prescribed throughout the entire treatment period.

Special Cases of Use.

Acne: the medicinal product should be administered at a dose of 50 mg daily for 6–12 weeks.

Sexually transmitted infections:

• Uncomplicated cervical, urethral, and rectal infections caused by Chlamydia trachomatis; uncomplicated genital infections caused by Neisseria gonorrhoeae (except anorectal infections in males); urethritis caused by Ureaplasma urealyticum: the medicinal product should be administered at a dose of 100 mg twice daily for 7 days;
• Epididymo-orchitis caused by Chlamydia trachomatis or Neisseria gonorrhoeae: the medicinal product should be administered at a dose of 100 mg twice daily for 10 days;
• Primary and secondary syphilis in patients without confirmed pregnancy and with penicillin allergy (as alternative therapy): the medicinal product should be administered at a dose of 200 mg twice daily for 14 days.

Epidemic relapsing fever, tick-borne relapsing fever: the medicinal product should be administered as a single dose of 100–200 mg depending on the severity of the disease.

Tropical malaria resistant to chloroquine: the medicinal product should be administered at a dose of 200 mg daily for at least 7 days.

Prophylaxis of malaria: the medicinal product should be prescribed at the following doses: adults – 100 mg daily; children aged 12 years – 2.2 mg/kg body weight daily up to a total daily dose of 100 mg. Prophylaxis may be initiated 1–2 days before travel to a malaria-endemic region. Prophylactic use of the medicinal product should continue daily during the stay in the malaria-endemic region and for 4 weeks after leaving the region. Current standards for malaria treatment should also be considered.

Prophylaxis of Japanese river fever: the medicinal product should be administered as a single dose of 200 mg.

Prophylaxis of traveler’s diarrhea in adults: the medicinal product should be administered: on the first day of travel – as a single dose of 200 mg or 100 mg every 12 hours; during subsequent days of travel – 100 mg daily. Information on use of the medicinal product for more than 21 days for prophylaxis is not available.

Prophylaxis of leptospirosis: the medicinal product should be administered at a dose of 200 mg once weekly throughout the stay in a leptospirosis-endemic region and 200 mg at the end of the trip. Information on use of the medicinal product for more than 21 days for prophylaxis is not available.

Special patient groups:

• Elderly patients: the medicinal product can be used at standard doses without special precautions. Doxycycline-Darnitsya may be the drug of choice for elderly patients, as its use is less associated with the development of esophageal irritation and ulcers;
• Patients with renal impairment: administration of the medicinal product at recommended doses does not lead to antibiotic accumulation (see section “Special Instructions”);
• Patients with hepatic impairment: see section “Special Instructions”.

Children.

The medicinal product is contraindicated in children under 12 years of age.

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

Use of tetracyclines during tooth development (in children under 12 years) may cause permanent discoloration of teeth (yellow-brown-gray). This adverse reaction is more common with prolonged use but may also occur with repeated short courses of treatment. Hypoplasia of enamel has also been reported.

Overdose.

Symptoms: intensification of adverse reactions.

Treatment: discontinuation of the medicinal product, gastric lavage, supportive and symptomatic therapy. Hemodialysis is ineffective.

Adverse Reactions.

Auditory and vestibular system disorders: sensation of ringing in the ears.

Gastrointestinal disorders: dyspepsia, abdominal pain, dysphagia, nausea, vomiting, diarrhea. Cases of esophagitis and ulcer formation have been reported in patients taking doxycycline capsules and tablets. Colitis caused by Clostridium difficile, enterocolitis, inflammatory lesions (with candidal overgrowth) in the anogenital area.

Hepatobiliary disorders: isolated cases of hepatotoxicity with transient elevations in liver function tests, liver dysfunction, jaundice, hepatitis, hepatic failure, pancreatitis have been reported.

Renal and urinary system disorders: increased blood urea levels, increased blood urea nitrogen (BUN) levels.

Endocrine system disorders: brown-black pigmentation of thyroid tissue microslides has been observed during prolonged use of tetracyclines. No thyroid dysfunction has been reported.

Metabolism and nutritional disorders: anorexia.

Nervous system disorders: headache, dizziness, bulging of the fontanelle in newborns, benign intracranial hypertension (pseudotumor cerebri), symptoms of which include blurred vision, scotoma, and diplopia; irreversible vision loss has been reported.

Cardiovascular disorders: arterial hypotension, tachycardia, pericarditis, flushing, Henoch-Schönlein purpura, dyspnea.

Blood and lymphatic system disorders: eosinophilia, hemolytic anemia, thrombocytopenia, neutropenia, porphyria.

Immune system disorders: hypersensitivity reactions, including anaphylaxis, anaphylactoid reactions, anaphylactic shock, anaphylactoid purpura, urticaria, angioneurotic edema, exacerbation of systemic lupus erythematosus, serum sickness, dyspnea, peripheral edema.

Skin and subcutaneous tissue disorders: skin rashes, including maculopapular and erythematous rashes; erythema multiforme, skin photosensitivity reactions, photo-onycholysis, exfoliative dermatitis, Stevens-Johnson syndrome (erythema multiforme major), Lyell's syndrome (toxic epidermal necrolysis), drug rash with eosinophilia and systemic symptoms (DRESS syndrome).

Musculoskeletal and connective tissue disorders: arthralgia, myalgia.

Infections and infestations: treatment with doxycycline may lead to superinfections such as staphylococcal enterocolitis, pseudomembranous colitis, candidiasis of the skin and mucous membranes, manifested as inflammation of the oral and pharyngeal mucosa (glossitis, stomatitis), acute inflammation of the external genital organs and vagina in women (vulvovaginitis), inflammation of the anogenital area.

Other: discoloration and hypoplasia of dental enamel during prolonged use of the drug.

Shelf life.

2 years.

Storage conditions.

Store in a place inaccessible to children, in the original packaging, at a temperature not exceeding 25 °C.

Packaging.

10 capsules in a blister pack; 1 or 2 blisters per carton; 1000 capsules in plastic containers.

Prescription status.

Prescription only.

Manufacturer.

JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's location and address of business activity.

13, Boryspilska Street, Kyiv, 02093, Ukraine.