Doxylar 100mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Doxylar* (Doxycycline) Tablets 100mg.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains doxycycline hydrochloride equivalent to doxycycline BP 100mg.
3 PHARMACEUTICAL FORM
Tablet.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Doxylar* is clinically useful in the treatment of a variety of infections caused by susceptible strains of Gram-positive and Gram-negative bacteria. These include pneumonia and other respiratory tract infections including acute and chronic bronchitis, genito-urinary infections and soft tissue infections caused by susceptible strains of Staphylococcus aureus and S albus, Streptococci, E coli, and the Klebsiella-aerobacter group.
As a member of the tetracycline group of antibiotics, Doxylar* may be expected to be useful in the treatment of infections which respond to other tetracyclines, eg: ophthalmic and gastrointestinal infections and a wide range of other infections such as psittacosis and infections due to susceptible strains of Bacteroides, Pasteurella, Brucella (in combination with streptomycin), Listeria, Rickettsia, H pertussis, B anthracis, C welshii, N meningitidis, Spirochaetes, and Donovania granulomatosis.
It may also be useful in treatment of acne vulgaris and acne conglobata.
The tablets can be used for the prophylaxis of malaria.
4.2 Posology and method of administration
An adequate volume of fluid should be taken when administering doxycycline capsules; this should preferably be taken by the patient whilst in an upright position and not immediately before going to bed.
Treatment should be continued at least 24 to 48 hours after fever and symptoms have subsided. When used in streptococcal infections, therapy should be continued for 10 days to prevent the development of rheumatic fever or glomerulo-nephritis.
Adults and children over 12 years of age who weigh over 50kg:
Usual recommended dose: 200mg on the first day followed by a maintenance dose of 100mg/day. For more severe infections 200mg should be given throughout the treatment.
Acute gonococcal anterior urethritis in males: Single dose of 300mg or 100mg, twice a day for 4 days (administered with food).
Acute gonococcal infections in the adult female: 100mg twice a day.
Primary and secondary syphilis (if penicillin allergic): 300mg a day in divided doses for at least 10 days.
For the prophylaxis of malaria: 100mg daily in adults and children over the age of 12 years. Treatment should commence 1-2 days before travelling to a malarial area and continue daily whilst travelling in malarial areas. On leaving a malarial area the traveller should continue treatment for 4 weeks. To ensure appropriate chemoprophylaxis and for current information on geographical resistance patterns, the current guidelines or the Malarial Reference Laboratory should be consulted, details of which can be found in the current version of the British National Formulary (BNF).
Elderly:
It is recommended that patients over 70 years of age are specifically instructed regarding the administration of doxycycline preparations.
Children:
Doxylar* (Doxycycline) Tablets must not be given to children under 12 years of age.
Method of administration: Oral.
4.3 Contraindications
Doxylar* should not be administered to patients who have shown hypersensitivity to tetracyclines.
• 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 long-term 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.
• Children under 12 years of age: 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 contra-indicated 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 over-growth 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 Interaction with other medicaments 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.
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.
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
Doxycycline is contra-indicated during pregnancy and lactation.
Tetracyclines taken during pregnancy may affect fetal skeletal development and cause permanent discolouration and malformation of teeth.
4.7 Effects on ability to drive and use machines
No known effects on ability to drive and use machines have been reported.
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 nonsusceptible 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.
Ear and labyrinth disorders: Tinnitus.
Hepato-biliary disorders: Transient increases in liver function tests, hepatitis, jaundice, hepatic failure and pancreatitis have been reported rarely.
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.
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.
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.
Skin and subcutaneous tissue disorders: Rashes including maculopapular and erythematous rashes occur, exfoliative dermatitis, erythema multiforme, Stevens- Johnson syndrome and toxic epidermal necrolysis.
Photosensitivity (see section 4.4).
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 at: www.mhra.gov.uk/yellowcard
4.9 Overdose
Acute overdosage with antibiotics is rare. In the event of overdosage, gastric lavage and other supportive measures are indicated.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Doxycycline is a broad-spectrum antibiotic.
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
In a cross-over trial on healthy volunteers the oral administration of 100mg Doxylar* produced the following serum levels:
Cmax = 2.04pg/ml chemical assay.
Cmax = 1.91pg/ml microbiological assay.
Tmax = 2 hours.
Doxycycline is almost completely absorbed and is not subject to presystemic metabolism, the mean bioavailability being approximately 93%. No significant metabolism occurs and Doxycycline is cleared intact by renal and biliary mechanisms. 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.
5.3 Preclinical safety data
Not required.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Furcellaran, povidone, magnesium stearate, colloidal silicon dioxide, stearic acid, talc, microcrystalline cellulose, hypromellose, dimethicone, propylene glycol and Opaspray M-1-7111 B white.
6.2 Incompatibilities
Not known.
6.3 Shelf life
36 months.
6.4 Special precautions for storage
Store in a cool dry place and protect from light.
6.5 Nature and contents of container
Securitainers.
Pack sizes: 10 and 50.
6.6 Special precautions for disposal
Not applicable.
MARKETING AUTHORISATION HOLDER
7
Ennogen Pharma Limited Unit G4,
Riverside Industrial Estate, Riverside Way,
Dartford DA1 5BS UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 40147/0031
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
13/10/2005
10 DATE OF REVISION OF THE TEXT
17/07/2015