Respilax Capsules

Doxycycline & Lactic Acid Bacillus Capsules

Each hard gelatin capsule contains :

Doxycycline Hyclate IP

equivalent to Doxycycline 100 mg

(as immediate-release pellets)

Lactic acid bacillus 5 billion spores

(as enteric coated pellets)

Colour : Titanium Dioxide IP

Excipients q.s.

Approved colours used in the capsule shell.

Capsule

4.1 Therapeutic indication

• For adult patients prone to intrabdominal bacterial infection & Antibiotic associated diarrhoea.
• Respiratory tract infections
• Urinary tract infections
• Sexually transmitted diseases
• Dermatological infections
• Ophthalmic infections
• Rickettsial infections

Other infections

Doxycycline Capsules are indicated for prophylaxis in the

following conditions : Scrub typhus, Travellers' diarrhoea, Leptospirosis.

4.2 Posology and method of administration

The capsules should be swallowed with plenty of fluid in either the resting or standing position and well before going to bed for the night to reduce the likelihood of oesophageal irritation and ulceration. If gastric irritation occurs, it is recommended that Doxycycline Capsules be given with food or milk. Studies indicate that the absorption of Doxycycline is not notably influenced by simultaneous ingestion of food or milk.

Posology

The usual dosage of Doxycycline for the treatment of acute infections in adults is 200 mg on the first day (as a single dose or in divided doses with a twelve-hour interval) followed by a maintenance dose of 100mg/day. In the management of more severe infections (particularly chronic infections of the urinary tract), 200 mg daily should be given throughout the treatment period. Exceeding the recommended dosage may result in an increased incidence of side effects. Therapy should be continued for at least 24 to 48 hours after the symptoms and fever have subsided. When used in streptococcal infections, therapy should be continued for 10 days to prevent the development of rheumatic fever or glomerulonephritis.

Dosage recommendations in specific infections :

Acne vulgaris

50 mg daily with food or fluid for 6 to 12 weeks.

Sexually transmitted diseases

100 mg twice daily for 7 days is recommended in the following infections : uncomplicated gonococcal infections (except anorectal infections in men); uncomplicated urethral, endocervical or rectal infection caused by Chlamydia trachomatis; non-gonococcal urethritis caused by Ureaplasma urealyticum. Acute epididymo-orchitis caused by Chlamydia trachomatis or Neisseria gonorrhoea 100 mg twice daily for 10 days.

Primary and secondary syphilis

300 mg a day in divided doses for at least 10 days.

Louse and tick-borne relapsing fevers

A single dose of 100mg or 200mg according to severity.

Treatment of chloroquine-resistant falciparum malaria

200 mg daily for at least 7 days. Due to the potential severity of the infection, a rapid- acting schizonticide such as quinine should always be given in conjunction with Doxycycline; quinine dosage recommendations vary in different areas

Prophylaxis of malaria

100 mg daily in adults and children over the age of 12 years. Prophylaxis can begin 1 - 2 days before travel to malarial areas. It should be continued daily during travel in the malarial areas and for 4 weeks after the traveller leaves the malarial area. For current advice on geographical resistance patterns and appropriate chemoprophylaxis, current guidelines or the Malaria Reference Laboratory should be consulted, details of which can be found in the British National Formulary (BNF).

For the prevention of scrub typhus

200 mg as a single dose.

For the prevention of travellers' diarrhoea in adults

200 mg on the first day of travel (administered as a single dose or as 100 mg every 12 hours) followed by 100 mg daily throughout the stay in the area. Data on the use of the drug prophylactically are not available beyond 21 days.

For the prevention of leptospirosis

200 mg once each week throughout the stay in the area and 200 mg at the completion of the trip. Data on the use of the drug prophylactically are not available beyond 21 days

Children aged 8 years to less than 12 years

The use of Doxycycline for the treatment of acute infections in children aged 8 years to less than 12 years should be carefully justified in situations where other drugs are not available, are not likely to be effective or are contraindicated.

In such circumstance, the doses for the treatment of acute infections are :

For children 45 kg or less

Initial dose : 4.4 mg/kg (in single or 2 divided doses) with maintenance dose : 2.2 mg/kg (in single or 2 divided doses). In the management of more severe infections, up to 4.4 mg/kg should be given throughout treatment.

For children, over 45 kg

Dose administered for adults should be used.

Children aged from birth to less than 8 years

Doxycycline should not be used in children aged younger than 8 years due to the risk of teeth discolouration.

Paediatric population

Not recommended

Elderly patients

Doxycycline may be prescribed in the usual dose with no special precautions. No dosage adjustment is necessary in the presence of renal impairment.

Renal impairment : Studies to date have indicated that administration of Doxycycline at the usual recommended doses does not lead to excessive accumulation of the antibiotic in patients with renal impairment.

The anti-anabolic action of the Tetracycline may cause an increase in blood urea. Studies to date indicate that this does not occur with the use of Doxycycline in patients with impaired renal function. Haemodialysis does not alter the serum half-life of Doxycycline.

4.3 Contraindications

• Hypersensitivity to the active substance, any of the tetracycline or to any of the excipients listed in the formulation.

• Sucrose intolerance : Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrose-isomaltase insufficiency should not take Doxycycline.

4.4 Special warnings and precautions for use

Paediatric population

The use of drugs of the tetracycline class during tooth development (last half of pregnancy; infancy and childhood to the age of 8 years) may cause permanent discolouration of the teeth (yellow-grey-brown). This adverse reaction is more common during long-term use of the drugs but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use Doxycycline in paediatric patients aged younger than 8 years only when the potential benefits are expected to outweigh the risks in severe or life- threatening conditions (e.g. Rocky Mountain spotted fever), particularly only when there are no adequate alternative therapies. Although the risk of permanent teeth staining is rare in children aged 8 years to less than 12 years, the use of Doxycycline should be carefully justified in situations where other drugs are not available, are not likely to be effective or are contraindicated.

Photosensitivity

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking Tetracycline, including Doxycycline. Patients likely to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs and treatment should be discontinued at the first evidence of skin erythema. Photoonycholysis has also been reported in patients receiving Doxycycline.

Use in patients with impaired hepatic function

Doxycycline should be administered with caution to patients with hepatic impairment or those receiving potentially hepatotoxic drugs. Abnormal hepatic function has been reported rarely and has been caused by both the oral and parenteral administration of Tetracycline, including Doxycycline.

Use in patients with renal impairment

Excretion of Doxycycline by the kidney is about 40%/72 hours in individuals with normal renal function. This percentage excretion may fall to a range as low as 1-5%/72 hours in individuals with severe renal insufficiency (creatinine clearance below 10ml/min). Studies have shown no significant difference in the serum half-life of Doxycycline in individuals with normal and severely impaired renal function. Haemodialysis does not alter the serum half-life of Doxycycline. The anti-anabolic action of the Tetracyclines may cause an increase in blood urea. Studies to date indicate that this anti-anabolic effect does not occur with the use of Doxycycline in patients with impaired renal function.

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. If serious skin reactions occur, Doxycycline should be discontinued immediately and appropriate therapy should be instituted.

Microbiological overgrowth

The use of antibiotics may occasionally result in overgrowth of non-susceptible organisms including Candida. If a resistant organism appears, the antibiotic should be discontinued and appropriate therapy instituted.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including Doxycycline, and has ranged in severity from mild to life-threatening. It is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents. Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibiotics, including Doxycycline, and has ranged in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C difficile. C difficile produces toxins A and B, which contribute to development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD should be considered in all patients who present with diarrhoea after antibiotic treatment. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

Oesophagitis

Instances of oesophagitis and oesophageal ulcerations have been reported in patients receiving capsule and tablet forms of drugs in the tetracycline class, including Doxycycline. Most of these patients took medications immediately before going to bed or with inadequate amounts of fluid.

Benign intracranial hypertension

Bulging fontanelles in infants have been reported in individuals receiving Tetracyclines. Benign intracranial hypertension (pseudotumor cerebri) has been associated with the use of Tetracyclines including Doxycycline. Benign intracranial hypertension (pseudotumor cerebri) is usually transient, however cases of permanent visual loss secondary to benign intracranial hypertension (pseudotumor cerebri) have been reported with Tetracyclines including Doxycycline. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize. Concomitant use of isotretinoin or other systemic retinoids and Doxycycline should be avoided because isotretinoin is also known to cause benign intracranial hypertension (pseudotumor cerebri).

Porphyria

There have been rare reports of porphyria in patients receiving Tetracyclines

Venereal disease

When treating venereal disease, where co-existent syphilis is suspected, proper diagnostic procedures, including dark-field examinations, should be utilised. In such cases monthly serological tests should be performed for at least four months.

Beta-haemolytic streptococci infections

Infections due to Group A beta-haemolytic streptococci should be treated for at least 10 days

Myasthenia gravis

Due to a potential for weak neuromuscular blockade, care should be taken in administering Tetracyclines to patients with myasthenia gravis.

Systemic lupus erythematosus

Tetracyclines can cause exacerbation of systemic lupus erythematosus (SLE).

Jarisch-Herxheimer reaction

Some patients with spirochete infections may experience a Jarisch-Herxheimer reaction shortly after Doxycycline treatment is started. Patients should be reassured that this is a usually self-limiting consequence of antibiotic treatment of spirochete infections

Methoxyflurane

Caution is advised in administering Tetracyclines with Methoxyflurane

4.5 Drugs interactions

The absorption of Doxycycline may be impaired by concurrently administered antacids containing aluminium, calcium, magnesium or other drugs containing these cations; Oral Zinc, Iron salts or Bismuth preparations. Dosages should be maximally separated. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving Doxycycline in conjunction with penicillin. There have been reports of prolonged prothrombin time in patients taking warfarin and Doxycycline. Tetracyclines depress plasma prothrombin activity and reduced doses of concomitant anticoagulants may be necessary.

The serum half-life of Doxycycline may be shortened when patients are concurrently receiving Barbiturates, Carbamazepine or Phenytoin. An increase in the daily dosage of Doxycycline should be considered

Alcohol may decrease the half-life of Doxycycline

A few cases of pregnancy or breakthrough bleeding have been attributed to the concurrent use of tetracycline antibiotics with oral contraceptives. Doxycycline may increase the plasma concentration of Ciclosporin. Co-administration should only be undertaken with appropriate monitoring. The concurrent use of Tetracyclines and Methoxyflurane has been reported to result in fatal renal toxicity. Concomitant use of isotretinoin or other systemic retinoids and Doxycycline should be avoided. Each of these agents used alone has been associated with benign intracranial hypertension (pseudotumor cerebri).

Laboratory test interactions

False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test. Drugs that induce hepatic enzymes such as Rifampicin may accelerate the decomposition of Doxycycline, thereby decreasing its half-life. Sub-therapeutic Doxycycline concentrations may result. Monitoring concurrent use is advised and an increase in Doxycycline dose may be required.

Ergotamine : There is an increased risk of Ergotism when Doxycycline is co-administered with Ergotamine.

Methotrexate : Doxycycline increases the risk of Methotrexate toxicity; prescribe with caution to patients on Methotrexate.

Quinapril contains Magnesium Carbonate and may interfere with the absorption of Doxycycline

4.6 Use in special populations

Pregnancy

Doxycycline is contraindicated in pregnancy. It appears that the risks associated with the use of Tetracyclines during pregnancy are predominantly due to effects on teeth and skeletal development.

Nursing mothers

Tetracyclines are excreted into milk and are therefore contraindicated in nursing mothers.

4.7 Effects on ability to drive and use machines

Visual disturbances such as blurring of vision may occur during treatment with Doxycycline and in such cases; patients must refrain from driving or operating machinery.

4.8 Undesirable effect

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com Website : http://www.zuventus.co.in/safety.aspx By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

Acute overdosage with antibiotics is rare. In the event of overdosage gastric lavage plus appropriate supportive treatment is indicated. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.

5.1 Mechanism of action

The main mechanism of action of Doxycycline is on protein synthesis. Doxycycline passes directly through the lipid bilayer of the bacterial cell wall and an energy dependent active transport system pumps the drug through the inner cytoplasmic membrane. Once inside the cell Doxycycline inhibits protein synthesis by binding to 30S ribosomes and prevents the addition of amino acids to the growing peptide chain. Doxycycline will impair protein synthesis in mammalian cells at very high concentrations but these cells lack the active transport system found in bacteria. Doxycycline is clinically effective in the treatment of a variety of infections caused by a wide range of gramnegative and gram-positive bacteria, as well as certain other micro- organisms

Lactic Acid bacillus spores, helps re-establish normal condition in the colon and has been shown to protect against antibiotic induced diarrhoea.

5.2 Pharmacodynamic properties

Doxycycline is clinically effective in the treatment of a variety of infections caused by a wide range of gramnegative and gram-positive bacteria, as well as certain other micro- organisms. Antimicrobial Spectrum

Gram-negative Bacteria

Acinetobacter species; Bartonella bacilliformis; Brucella species; Campylobacter fetus; Enterobacter aerogenes; Escherichia coli; Francisella tularensis; Haemophilus ducreyi; Haemophilus inuenza; Klebsiella granulomatis; Klebsiella species; Neisseria gonorrhoeae; Shigella species; Vibrio cholerae; Yersinia pestis.

Gram-positive Bacteria

Bacillus anthracis; Streptococcus pneumoniae.

Anerobic Bacteria

Clostridium species; Fusobacterium fusiforme; Propionibacterium acnes

Other Bacteria

Norcardiae and other aerobic Actinomyces species; Borrelia recurrentis; Chlamydophila psittaci; Chlamydia trachomatis; Mycoplasma pneumonia; Rickettsiae; Treponema pallidum; Treponema pallidum subspecies pertenue; Ureaplasma urealyticum.

Parasites

Balantidium coli; Entamoeba species; Plasmodium falciparum. Lactic acid bacillus is a pro biotic. It is known to have the following actions. Prevention and reduction of intestinal tract infections Enhances immune response Maintains mucosal integrity

5.3 Pharmacokinetic properties

Absorption

Doxycycline is almost completely absorbed and is not subject to presystemic metabolism, the mean bioavailability being approximately 93%. Absorption is rapid (effective concentrations are attained as from the first hour), and the peak serum concentration occurs after 2 to 4 hours. Almost all of the product is absorbed in the upper part of the digestive tract. Absorption is not modied by administration with meals, and milk has little effect.

Distribution

Tissue distribution is good and Doxycycline has a strong affinity for renal and lung tissue. The volume of distribution for Doxycycline ranges from 0.9 - 1.8 lkg-1.

In adults, an oral dose of 200 mg results in;

• A peak serum concentration of more than 3 μg/ml.

• A residual concentration of more than 1 μg/ml after 24 hours.

• A serum half-life of 16 to 22 hours.

Protein binding varying between 82 and 93% (labile binding) intra- and extracellular diffusion is good. With usual dosages, effective concentrations are found in the ovaries, uterine tubes, uterus, placenta, testicles, prostate, bladder, kidneys, lung tissue, skin, muscles, lymph glands, sinus secretions, maxillary sinus, nasal polyps, tonsils, liver, hepatic and gallbladder bile, gallbladder, stomach, appendix, intestine, omentum, saliva and gingival uid. Doxycycline is transferred into breast milk. Only small amounts are diffused into the cerebrospinal uid.

Biotransformation

No significant metabolism occurs.

Elimination

Doxycycline is cleared intact by renal and biliary mechanisms The antibiotic is concentrated in the bile. About 40% of the administered dose is eliminated in 3 days in active form in the urine and about 32% in the faeces. Urinary concentrations are roughly 10 times higher than plasma concentrations at the same time. In the presence of impaired renal function, urinary elimination decreases, faecal elimination increases and the half-life remains unchanged. The half-life is not affected by haemodialysis. Lactic acid bacillus, is a non pathogenic live spores which can germinate in intestine, survives gastric acidity and proliferate with inherent potentiality.

6.1 Animal toxicology or pharmacology

No known animal toxicology data.

Doxycycline is a broad-spectrum antibacterial. It is derived synthetically from Oxytetracycline. Lactic acid bacillus is a non-pathogenic, gram-positive, spore-forming, Lactic-acid producing bacillus. It forms Lactic acid as the main end product of Carbohydrate metabolism. They are commercialized as probiotics. In humans, they live as commensals in oral cavities, gastrointestinal tracts (GIT), and vagina.

8.1 Incompatibilities

Not applicable

8.2 Shelf life

Refer on the pack.

8.3 Packaging information

Alu strip of 10 capsules.

8.4 Storage and handling instructions

Store below 25°C. Protect from light & moisture.

Keep out of reach of children.

Capsule should be swallowed whole & not to be opened, chewed or crushed.

All patients taking Doxycycline should be advised

• To avoid excessive sunlight or artificial ultraviolet light while receiving Doxycycline and to discontinue therapy if phototoxicity (e.g., skin eruption, etc.) occurs. Sunscreen or sunblock should be considered.
• To drink fluids liberally along with Doxycycline to reduce the risk of esophageal irritation and ulceration.
• That the absorption of Tetracyclines is reduced when taken with foods, especially those which contain calcium. However, the absorption of Doxycycline is not markedly influenced by simultaneous ingestion of food or milk.
• That the absorption of Tetracyclines is reduced when taking bismuth subsalicylate.
• That the use of Doxycycline might increase the incidence of vaginal candidiasis.

Patients should be counselled that antibacterial drugs, including Doxycycline should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Doxycycline is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Doxycycline or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibacterial drugs, which usually ends when the antibacterials are discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible.