Doxycycline Capsules Bp 100mg
1 Name of the Medicinal Product
DOXYCYCLINE CAPSULES BP 100mg 2 Qualitative and quantitative composition
Each capsule contains Doxycycline hyclate equivalent to 100mg of Doxycycline base. For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Green hard gelatin capsules printed “C” and “DW” in black.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Doxycycline Capsules are used in the treatment of a variety of infections caused by susceptible strains of Gram-positive and Gram-negative bacteria and certain other micro-organisms.
1) Respiratory tract infections: Pneumonia and other lower tract respiratory tract infections due to susceptible strains of Streptococcus pneumoniae, Haemophilia influenzae, Klebsiella pneumoniae and other organisms. Mycoplasma pneumoniae pneumonia. Treatment of chronic bronchitis. Sinusitis.
2) Urinary tract infections: Infections caused by susceptible strains of Klebsiella species, Enterobacter species. Escherichia coli, Streptococcus faecalis and other organisms.
3) Sexually transmitted diseases: Infections due to Chlamydia trachomatis including uncomplicated urethral, endocervical or rectal infections. Non-gonococcal, urethritis caused by Ureaplasma urealyticum. Chancroid infections due to alymmatobacterium granulomatis. Alternative drug in the treatment of gonorrhoea and syphilis.
4) Dermatological infections: Acne vulgaris when antibiotic therapy is considered necessary.
Since doxycycline is a member of the tetracycline series of antibiotics, it may be expected to be useful in the treatment of infections which respond to other tetracyclines, such as:
1) Ophthalmic infections: Due to susceptible strains of gonococci, staphylococci and Haemophilus influenzae. Doxycycline Capsules are indicated in the treatment of trachoma, although the infectious agent is not always eliminated, as judged by immunofluorescence.
2) Rickettsial infections: Rocky Mountain spotted fever, typhus group, Q fever and Coxiella endocarditis and tick fevers.
3) Miscellaneous: Psittacosis, cholera, meliodosis, leptospirosis, other infections due to susceptible strains of Yersinia species, Brucella species (in combination with
Streptomycin), Clostridium species, Francisella tularensis and chloroquine-resistant falciparum malaria.
4) Doxycycline Capsules are indicated for prophylaxis in the following conditions: Scrub typhus, travellers diarrhoea (enterotoxigenic Escherichia coli), leptospirosis.
4.2 Posology and method of administration
Posology
Adults: The usual dose of Doxycycline Capsules for the treatment of acute infections in adults is 200mg on the first day (administered as a single dose or divided into two equal 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), 200mg 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 at least 24-48 hours after 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.
Specific infections:
Acne vulgaris: 50mg daily with food or fluid for 6-12 weeks.
Sexually transmitted diseases: 100mg 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 realyticum. Acute epididymo-orchitis caused by Chlamydia trachomatis or Neisseria gonorrhoeae 100mg twice daily for 10 days.
Primary and secondary syphilis: 300mg a day in divided doses for at least 10 days. Louse-borne and tick-borne relapsing fevers: A single dose of 100mg or 200mg according to severity.
Chloroquine-resistant falciparum malaria: 200mg 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.
For the prevention of scrub typhus: 200mg as a single dose.
For the prevention of travellers’ diarrhoea in adults: 200mg on the first day of travel (administered as a single dose or as 100mg every 12 hours) followed by 100mg 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: 200mg once each week throughout the stay in the area and 200mg at the completion of the trip. Data on the use of the drug prophylactically are not available beyond 21 days.
Paediatric population: Not recommended.
Elderly: 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 tetracyclines 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.
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.
4.3 Contraindications
• Hypersensitivity to the active substance, any of the tetracyclines or to any of the excipients listed in section 6.1.
• The use of drugs of the tetracycline class during tooth development (pregnancy, infancy and childhood to the age of 12 years) may cause permanent discolouration of the teeth (yellow-grey-brown). This adverse reaction is more common during longterm use of the drugs but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Doxycycline is contra-indicated in these groups of patients.
• Paediatric population: Contraindicated in children under the age of 12 years. As with other tetracyclines, doxycycline forms a stable calcium complex in any bone-forming tissue. A decrease in the fibula growth rate has been observed in prematures given oral tetracyclines in doses of 25mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. (See above about use during tooth development).
• Pregnancy: Doxycycline is contra-indicated 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. (See above about use during tooth development).
• Nursing mothers: Tetracylines are excreted into milk and are therefore contraindicated in nursing mothers. (See above about use during tooth development).
4.4 Special warnings and precautions for use
Photosensitivity: Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines, 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.
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 tetracyclines, 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.
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.
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.
Bulging fontanelles in infants and benign intracranial hypertension in juveniles and adults have been reported in individuals receiving full therapeutic drugs. These conditions disappeared rapidly when the drug was discontinued.
Porphyria: There have been rare reports of porphyria in patients receiving tetracyclines.
Venereal disease: When treating venereal diseases, where coexistent syphilis is suspected, proper diagnostic procedures, including dark-field examinations, should be utilised. In all such cases monthly serological tests should be made 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 erythematous: Tetracyclines can cause exacerbation of systemic lupus erythematosus (SLE).
Methoxyflurane: Caution is advised in administering tetracyclines with methoxyflurane (see section 4.5).
4.5 Interactions with other medicinal products and other forms of interaction
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.
Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving doxycycline in conjunction with penicillin.
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. Phenobarbital, carbamazepine, primidone and phenytoin may increase the metabolism of doxycycline (reduced half-life). An increase in the daily dosage of doxycycline should be considered.
Alcohol may decrease the half-life of doxycycline.
The concurrent use of tetracyclines and methoxyflurane has been reported to result in fatal renal toxicity. See section 4.4.
Doxycycline may increase the plasma concentration of ciclosporin. Coadministration should only be undertaken with appropriate monitoring.
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.
Laboratory test interactions
False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.
4.6 Fertility, pregnancy and lactation
See “Contra-indications”, section 4.3.
4.7 Effects on ability to drive and use machines
The effect of doxycycline on the ability to drive or operate heavy machinery has not been studied. There is no evidence to suggest that doxycycline may affect these abilities.
4.8 Undesirable effects
The following adverse reactions have been observed in patients receiving tetracyclines, including doxycycline.
Hypersensitivity reactions, including anaphylactic shock, anaphylaxis, anaphylactoid reactions, anaphylactoid purpura, hypotension, pericarditis, angioneurotic oedema, exacerbation of systemic lupus erythematosus, dyspnoea, serum sickness, peripheral oedema, tachycardia and urticaria.
Infections and infestations: As with all antibiotics, overgrowth of non-susceptible organisms may cause candidiasis, glossitis, staphylococcal enterocolitis, pseudomembranous colitis (with Clostridium difficile overgrowth) and inflammatory lesions (with candidal overgrowth) in the anogenital region.
Blood and lymphatic system disorders: Haemolytic anaemia, thrombocytopenia, neutropenia, porphyria and eosinophilia have been reported with tetracyclines.
Endocrine disorders: When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid tissue. No abnormalities of thyroid function are known to occur.
Nervous system disorders: Headache. Bulging fontanelles in infants and benign intracranial hypertension in juveniles and adults have been reported in some individuals receiving full therapeutic dosages of tetracyclines. These are reversible on stopping the drug. Symptoms include blurring of vision, scotomata and diplopia. Permanent visual loss has been reported.
Ear and labyrinth disorders: Tinnitus.
Gastrointestinal disorders: Gastro-intestinal symptoms are usually mild and seldom necessitate discontinuation of treatment. Abdominal pain, stomatitis, anorexia, nausea, vomiting, diarrhoea, dyspepsia and rarely dysphagia. Oesophagitis and oesophageal ulceration have been reported in patients receiving doxycycline. A significant proportion of these cases has occurred with the hydrochloride salt in the capsule form. (See section 4.4). Tetracyclines may cause discoloration of teeth and enamel hypoplasia, but usually only after long-term use.
Hepato-biliary disorders: Transient increases in liver function tests, hepatitis, jaundice, hepatic failure and pancreatitis have been reported rarely.
Skin and subcutaneous tissue disorders: Rashes including maculopapular and erythematous rashes occur, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis, photo-onycholysis.
Photosensitivity (see section 4.4).
Musculo-skeletal, connective tissue and bone disorders: Arthralgia and myalgia.
Renal and urinary disorders: Increased blood urea. (See section 4.4).
Reproductive system and breast disorders: vaginitis.
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 the Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard
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 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: tetracyclines, ATC code: J01AA02
Doxycycline is primarily a bacteriostatic antibiotic.
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.
5.2 Pharmacokinetic properties
Absorption
Doxycycline is almost completely absorbed and is not subject to presystemic metabolism, the mean bioavailability being approximately 93%.
Distribution
Tissue distribution is good and Doxycycline has a strong affinity for renal and lung tissue. Plasma protein binding is in the range 82-93% and Doxycycline is transferred into breast milk. The volume of distribution for doxycycline ranges from 0.9-1.8 lkg-1 and the plasma half life ranges from 18-22 hours.
Biotransformation No significant metabolism occurs.
Elimination
Doxycycline is cleared intact by renal and biliary mechanisms.
5.3 Preclinical safety data
Not applicable.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Also contains: Gelatin
Magnesium stearate Shellac glaze Sodium lauryl sulfate Starch
Quinoline Yellow (E104) Erythrosine (E127)
Patent Blue V (E131) Titanium Dioxide (E171) Iron oxide black (E172) Propylene glycol
6.2 Incompatibilities
None known.
6.3 Shelf life
PVC Blister packs 5 years.
All other containers 4 years.
6.4 Special precautions for storage
Store below 25°C in a dry place.
6.5 Nature and contents of container
The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers with polyfoam wad or polyethylene ullage filler and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass containers with screw caps and polyfoam wad or cotton wool.
The product may also be supplied in blister packs in cartons:
a) Carton: Printed carton manufactured from white folding box board.
b) Blister pack: (i) 250pm white rigid PVC. (ii) Surface printed 20pm hard temper aluminium foil with 5-7g/M2 PVC and PVdC compatible heat seal lacquer on the reverse side.
Pack sizes: 7s, 8s, 10s, 14s, 16s, 28s, 30s, 50s, 56s, 60s, 84s, 90s, 100s, 112s, 120s, 168s, 180s
6.6 Special precautions for disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Actavis UK Limited (Trading style: Actavis)
Whiddon Valley BARNSTAPLE N Devon EX32 8NS
8 MARKETING AUTHORISATION NUMBER(S)
PL 00142/0407
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
2 April 1997
10 DATE OF REVISION OF THE TEXT
19/05/2016