- Approval Id
- d5b99a1fd14d2fe7
- Drug Approval Emc Name
- Tetracycline 250 mg Tablets
- Drug Name
- Tetracycline 250 mg Tablets
- Company Name
- Sigma Pharmaceuticals PLC (Special Concept Development / RxFarma)
- Company Address
- HD House, Imperial Way, North Watford, Hertfordshire, WD24 4LQ, UK
- Company Website
- http://www.sigmaplc.com/our-product-offerings/rxfa
- Company Telephone
- +44 (0)800 358 0163
- Company Medical Info Direct Line
- +44 (0)800 358 0163
- Company Medical Info Email
- medinfo@rxfarma.co.uk
- Company Customer Care Direct Line
- +44 (0)800 358 0163
- Atc Code
- J01AA07
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Special Concept Development (UK) Ltd
Units 1-7 Colonial Way
Watford
Hertfordshire
WD24 4YR
- Authorisation Number
- PL 36722/0018
- Authorisation Date
- 14/03/2007
- Instruction Authorisation Holder
- Special Concept Development (UK) Ltd
Units 1-7 Colonial Way
Watford
Hertfordshire
WD24 4YR
- Instruction Authorisation Number
- PL 36722/0018
- Instruction Authorisation Date
- 14/03/2007
- Instruction Composition
- Each tablet contains Tetracycline Hydrochloride 250.0 mg.
Excipient(s) with known effect-
For the full list of excipients, see section 6.1.
- Instruction Dosage Form
- Coated tablet.
Orange, sugar coated tablet with no markings.
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
Tetracycline is a bacteriostatic broad-spectrum antibiotic, active against a wide variety of gram-positive and gram-negative organisms.
Infections caused by tetracycline-sensitive organisms include:
1) Respiratory tract infections: Pneumonia and other lower respiratory tract infections due to susceptible strains of Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae and other organisms. Mycoplasma pneumoniae pneumonia. Treatment of chronic bronchitis (including the prophylaxis of acute exacerbations) and whooping cough.
2) Urinary tract infections: Caused by susceptible strains of the 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. Tetracycline is also indicated in chancroid, granuloma inguinale and lymphogranuloma venereum.
4) Tetracycline is an alternative drug in the treatment of penicillin resistant gonorrhoea and syphilis.
5) Skin infections: Acne vulgaris when antibiotic therapy is considered necessary and severe rosacea.
6) Ophthalmic infections: Trachoma, although the infectious agent, as judged by immunofluorescence, is not always eliminated. Inclusion conjunctivitis may be treated with oral tetracycline alone or in combination with topical agents.
7) Rickettsial infections: Rocky mountain spotted fever, typhus group, Q fever and Coxiella endocarditis and tick fevers.
8) Other infections: Stagnant loop syndrome. Psittacosis, brucellosis (in combination with streptomycin), cholera, bubonic plague, louse and tick-borne relapsing fever, tularaemia, glanders, melioidosis and acute intestinal amoebiasis (as an adjunct to amoebicides).
Tetracycline is an alternative drug in the treatment of leptospirosis, gas-gangrene and tetanus.4.2 Posology and method of administration
\*\*\*Posology\*\*\*
Tetracycline should be given one hour before or two hours after meals, since food and some dairy products interfere with absorption. The tablets should be taken with a good drink of water.Therapy should be continued for up to three days after symptoms have subsided.
All infections due to group a beta-haemolytic streptococci should be treated for at least 10 days.
Adults, the elderly and children over 12 years: The minimum recommended dosage is 250mg every six hours. Therapeutic levels are attained more rapidly by the administration of 500mg initially, followed by 250mg every six hours. For severe infections, the dosage may be increased to 500mg every six hours
Children under 12 years of age: Contraindicated in this age group.
Elderly: Usual adult dose. Caution should be observed as subclinical renal insufficiency may lead to drug accumulation.
Renal impairment: In general tetracyclines are contraindicated in renal impairment and the dosing recommendations only apply if use of this class of drug is deemed absolutely essential. Total dosage should be decreased by reduction of recommended individual doses and/or by extending time intervals between doses.
Dosage recommendations in specific infections:
Skin infections: 250 – 500mg daily in single or divided doses should be administered for at least three months in the treatment of acne vulgaris and severe rosacea.
Brucellosis: 500mg tetracycline four times daily accompanied by streptomycin.
Sexually transmitted diseases: 500mg four times daily for seven days is recommended in the following infections: Uncomplicated gonoccal infections (except anorectal infections in man); uncomplicated urethral, endocervical or rectal infection caused by Chlamydia trachomatis; non-gonoccal urethritis caused by Ureaplasma urealyticum.
Acute epididymo-orchitis caused by Chlamydia trachomatis, or Neisseria gonorrhoea, 500mg four times daily for 10 days. Primary and secondary syphilis: 500mg four times daily for 15 days. Syphilis of more than one year's duration, (latent syphilis of uncertain or more than one year's duration, cardiovascular or late benign syphilis) except neurosyphilis, should be treated with 500mg, four times daily for 30 days.
Patient compliance with this regimen may be difficult so care should be taken to encourage optimal compliance. Close follow-up including laboratory tests, is recommended.
\*\*\*Method of Administration\*\*\*
For oral administration4.3 Contraindications
Known hypersensitivity to any of the tetracyclines or any of the other constituents in the formulation; chronic renal or hepatic dysfunction, renal impairment, particularly if severe, pregnancy, lactation, systemic lupus erythematosus, children under 12 years (see sections 4.4, 4.6 and 4.8) ; pregnancy and breastfeeding women.
Benign intracranial hypertension has been reported following the concomitant use of tetracyclines and Vitamin A or retinoids and therefore concurrent use should be contraindicated (see section 4.5 and 4.8).4.4 Special warnings and precautions for use
Tetracyclines depress plasma prothrombin activity; therefore reduced dosages of concurrent anticoagulants may be required.
The use of tetracyclines if administered during tooth development, in the last half of pregnancy and in children under the age of 12 years may cause permanent tooth discolouration (yellow-grey-brown) (see sections 4.3, 4.6 and 4.8) Enamel hypoplasia has also been reported. This adverse reaction is more common during long-term use of the drug but has been observed following repeated short-term courses.
The use of tetracycline in general is contraindicated in renal impairment due to excessive systemic accumulation and used with caution in patients with hepatic impairment or those receiving drugs which may have hepatotoxic effects; high doses should be avoided. High doses of tetracyclines have been associated with a syndrome involving fatty liver degeneration and pancreatitis. They should not be used with penicillins and they should not be discontinued if supra-infection occurs.
The anti-anabolic action of tetracyclines may cause an increase in BUN. While this is not a problem in those with normal renal function, in patients with significantly impaired renal function, higher serum levels of tetracycline may lead to azotaemia, hyperphosphataemia and acidosis.
In long-term therapy, periodic laboratory evaluation of organ systems, including haemopoietic, renal and hepatic studies should be performed.
Tetracycline is probably porphyrinogenic. Advice of a porphyria specialist should be sought for tetracycline use in patients with acute porphyria.
Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, patients should be warned to avoid direct exposure to natural or artificial sunlight and that treatment should be discontinued at the first evidence of skin erythema or skin discomfort.
SLE (systemic lupus erythematosus) can be exacerbated by the use of tetracyclines.
Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment (including several weeks after treatment) with Tetracycline tablets, may be symptomatic of Clostridium difficile-associated disease (CDAD). CDAD may range in severity from mild to life threatening, the most severe form of which is pseudomembranous colitis (see section 4.8). It is therefore important to consider this diagnosis in patients who develop serious diarrhoea during or after treatment with Tetracycline tablets. If CDAD is suspected or confirmed Tetracycline tablets should be stopped immediately and appropriate therapy initiated without delay. Anti-peristaltic drugs are contraindicated in this clinical situation.
Cross resistance between tetracyclines may develop in micro-organisms and cross- sensitisation patients. The use of antibiotics may occasionally result in the overgrowth of nonsusceptible organisms including Candida (see section 4.8). Constant observation of the patient is essential. Tetracycline should be discontinued and appropriate therapy instituted if there are signs/symptoms of overgrowth of resistant organisms including candida, enteritis, glossitis, stomatitis, vaginitis, pruritis ani or staphylococcal enterocolitis.
Patients with rare hereditary problems of fructose or galactose intolerance, the LAPP lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
When treating venereal disease, where co-existent syphilis is suspected, proper diagnostic procedures should be utilised. In all such cases, monthly serological tests should be made for at least four months.
Care is advised when administered to patients with myasthenia gravis. Tetracycline may increase muscle weakness in patients with myasthenia gravis.
The tablet coating contains Sunset Yellow (E110) which may cause allergic reactions.
Sodium
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.
Sucrose
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.4.5 Interaction with other medicinal products and other forms of interaction
Tetracycline should not be used with penicillins.
Tetracyclines depress plasma prothrombin activity and reduced doses of concomitant anticoagulants such as coumarins and phenindione may be required. Tetracycline may prolong the action of coumarin anticoagulants.
Absorption of tetracycline from the gastrointestinal tract is impaired by the concomitant administration of di and trivalent cations such as iron, calcium, zinc salts, bismuth, magnesium and aluminium salts. Absorption of zinc and oral iron is impaired by tetracycline. Administration of medicinal products containing these cations and tetracycline should be maximally separated by at least two to three hours. The following should be avoided when taking tetracycline: antacids, bismuth containing ulcer-healing drugs, drugs such as quinapril tablets which contain magnesium carbonate and didanosine which contains calcium and magnesium excipients.
Absorption of tetracycline is impaired by food, milk and dairy products, sucralfate, tripotassium dicitratobismuthate and strontium ranelate (manufacturer of strontium ranelate advises avoid concomitant use).
There have been reports of nephrotoxicity (increased blood urea nitrogen and serum creatinine) and death in some cases when tetracycline therapy has been combined with methoxyflurane.
Tetracycline may increase the hypoglycaemic effects of insulin and sulphonylureas in patients with diabetes mellitus.
The absorption of tetracycline may be reduced by the concomitant administration of sucralfate. Separating administration should be considered.
Absorption of tetracycline is possibly reduced by colestipol, colestyramine and antidiarrhoeal preparations such as kaolin-pectin and bismuth subsalicylate
Combination of tetracyclines with diuretics may be detrimental to renal function and may aggravate nephrotoxicity by volume depletion.
Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline in conjunction with penicillin.
Tetracycline may cause an increase in serum lithium levels. Tetracycline may cause an increase in serum digoxin levels.
Tetracycline may cause an increase in the risk of methotrexate toxicity. Regular monitoring of toxicity is necessary when taken concurrently.
Increased risk of ergotism when tetracycline given with ergotamine and methysergide.
A few cases of pregnancy or breakthrough bleeding have been attributed to the concurrent use of tetracycline with oral contraceptives and alternative contraceptive advice should be sought where necessary.
Tetracycline reduces plasma concentration of atovaquone.
There is a possible increased risk of benign intracranial hypertension with tetracyclines and retinoids (acitretin, isotretinoin, tretinoin). Concomitant use should be avoided.
Antibacterials inactivate oral typhoid vaccine. Vaccination should not commence within 3 days after completing treatment with any antibacterial agents. Also, it is preferable that antibacterial therapy should not commence within 3 days after the last dose of vaccine.4.6 Fertility, pregnancy and lactation
\*\*\*Pregnancy\*\*\*
Not to be used in pregnancy unless essential to the patient's welfare. Tetracyclines cross the placenta and may have toxic effects on foetal tissues, particularly on skeletal development (see sections 4.3, 4.4 and 4.8). Tetracycline may be deposited in deciduous and permanent teeth giving permanent discolouration. It should not be used during pregnancy or lactation.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the foetus.
The use of tetracycline compounds during pregnancy has been associated with reports of maternal liver toxicity.
Use in newborns, infants and children: All tetracyclines form a stable calcium complex in any bone-forming tissue.
A decrease in fibula growth rate has been observed in premature infants given oral tetracycline in doses of 25mg/kg every 6 hours. This reaction was reversed when drug was discontinued.
\*\*\*Breast-feeding\*\*\*
Tetracyclines are also excreted in breast milk and are therefore contraindicated in nursing mothers.4.7 Effects on ability to drive and use machines
No significant effect.4.8 Undesirable effects
There are no modern clinical studies available that can be used to determine the frequency of undesirable effects.
The following convention has been utilised for the classification of frequency. Very common ≥ 1/10; common ≥ 1/100 and < 1/10; uncommon ≥ 1/1000 and < 1/100; rare ≥ 1/10,000 and < 1/1000; very rare < 1/10,000; not known (cannot be estimated from the available data).
| | | | | | |
| --- | --- | --- | --- | --- | --- |
| \*\*System Organ Class\*\* | \*\*Common\*\* ≥ \*\*1/100 to < 1/10\*\* | \*\*Uncommon\*\* ≥ \*\*1/1 000 to < 1/100\*\* | \*\*Rare\*\* ≥ \*\*1/10 000 to < 1/1 000\*\* | \*\*Very Rare\*\* \*\*< 1/10 000\*\* | \*\*Frequency not known (cannot be estimated from available data)\*\* |
| \*\*Infections and infestations:\*\* | | | | | As with all antibiotics, overgrowth of resistant organisms (Candida albicans, in particular); this may cause candidiasis, pseudomembranous colitis (\*Clostridium difficile\* overgrowth), glossitis, stomatitis, vaginitis or staphylococcal enterocolitis (caused by resistant staphylococci), rectal and vaginal irritation, inflammatory lesions (with candida overgrowth) in the anogenital regions (see section 4.4) |
| \*\*Blood & lymphatic system disorders\*\* | | | Haemolytic anaemia, thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and eosinophilia | | |
| \*\*Immune system disorders\*\* | | | | | Hypersensitivity reactions including rash, exfoliative dermatitis, Stevens- Johnson syndrome, urticaria, angioedema, toxic epidermal necrolysis, anaphylaxis, anaphylactoid purpura, pericarditis, exacerbation of systemic lupus erythematosus (see sections 4.3 and 4.8), fixed drug eruptions |
| \*\*Endocrine disorders:\*\* | | | | | When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discolouration of the thyroid gland. No abnormalities of thyroid function are known to occur. |
| \*\*Nervous system disorders\*\* | | | | | Headache, dizziness PT Cerebellar syndrome Cerebellar syndrome (eg. ataxia, dysarthria, gait impairment, nystagmus and tremor), which may resolve upon discontinuation of the drug, have been observed with Pylera. |
| \*\*Eye disorders\*\* | | | | | visual disturbances, permanent visual loss |
| \*\*Ear & labyrinth disorders\*\* | | | Impaired hearing | | |
| \*\*Vascular disorders\*\* | | | | | Bulging fontanelles in infants; benign intracranial hypertension in juveniles and adults (see section 4.3). Treatment should cease if evidence of raised intracranial pressure develops, such as severe or persistent headache, dizziness, tinnitus and visual disturbances including blurred vision, scotomata and diplopia. While the condition and related symptoms usually resolve soon after discontinuation of the tetracycline, the possibility of permanent sequelae exists. |
| \*\*Gastrointestinal disorders\*\* | | | Dysphagia. Oesophagitis and oesophageal ulceration (most of these patients took medication immediately before going to bed) have been reported in patients taking oral tetracyclines in solid dose form, usually where medication was taken immediately before retiring for bed or with inadequate fluids. | | Gastrointestinal irritations, nausea, vomiting, diarrhoea, pancreatitis, anorexia, abdominal discomfort, permanent tooth discolouration and enamel hypoplasia in children (see sections 4.3, 4.4 and 4.6). Tooth discolouration has also been seen in adults. If gastric irritation occurs, tablets should be taken with food. |
| \*\*Hepatobiliary disorders:\*\* | | | Transient increases in liver function test values, hepatitis, jaundice, hepatic failure | | Hepatotoxicity associated with fatty liver. |
| \*\*Skin & subcutaneous tissue disorders\*\* | | | Serious skin reactions | | Erythematous and maculo-papular rashes, photosensitivity (patients exposed to direct sunlight or ultraviolet light should be advised to discontinue treatment if any skin reaction occurs), pruritis, bullous dermatoses, skin discolouration |
| \*\*Musculoskeletal, connective tissue & bone disorders\*\* | | | | | Increased muscle weakness in patients with myasthenia gravis (see section 4.4). |
| \*\*Renal & urinary disorders\*\* | | | Acute renal failure, nephritis | | Raised serum urea, renal dysfunction, especially in patients with pre-existing renal impairment |
\*\*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 or search for MHRA Yellow Card in the Google Play or Apple App Store..4.9 Overdose
\*Symptoms:\*
There may be nausea and vomiting.
Crystalluria and haematuria may occur following very large doses.
Hypersensitivity reactions may occur.
\*Treatment:\*
There is no specific antidote.
Gastric decontamination is not necessary.
Give oral fluids for severe vomiting and diarrhoea if required.
Manage anaphylaxis reactions conventionally.
Single brief convulsions do not require treatment. If frequent or prolonged control with intravenous diazepam or lorazepam.
General symptomatic therapy as indicated by the patient's clinical condition.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antibacterials for systemic use, tetracyclines
ATC code: J01A A07
Mechanism of action
Tetracycline is a broad spectrum antibiotic. It is mainly bacteriostatic and acts by interfering with bacterial protein synthesis.
Tetracyclines are taken up into sensitive bacterial cells by an active transport process. Once within the cell they bind reversibly to the 30S subunit of the ribosome, preventing the binding of aminoacyl transfer RNA and inhibiting protein synthesis and hence cell growth. Although tetracyclines also inhibit protein synthesis in mammalian cells they are not actively taken up, permitting selective effects on the infecting organism.
The deposition of tetracycline in and discolouration of teeth is a problem if given to children or during pregnancy.
Hepatotoxicity may be a problem in patients with impaired liver function.
Susceptibility testing breakpoints
MIC (minimum inhibitory concentration) interpretive criteria for susceptibility testing have been established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for tetracycline and are listed here: https://www.ema.europa.eu/documents/other/minimum-inhibitoryconcentration-mic-breakpoints\\_en.xlsx5.2 Pharmacokinetic properties
Absorption
Most tetracyclines are incompletely absorbed from the gastrointestinal tract, about 60- 80% of a dose of tetracycline usually being available. The degree of absorption is diminished by the presence of divalent and trivalent metal ions with which tetracyclines form stable insoluble complexes and to a variable degree by milk or food. Formulation with phosphate may enhance the absorption of tetracycline.
Plasma concentrations will depend upon the degree of absorption. Administration of tetracycline 500mg every 6 hours generally produces steady-state concentrations of 4- 5µg/ml. Peak plasma concentrations occur about 1-3 hours after ingestion. Higher concentrations can be achieved after intravenous administration; concentrations may be higher in women than in men.
Distribution
They are widely distributed throughout the body tissues and fluids. Concentrations in cerebrospinal fluid are relatively low, but may be raised if the meninges are inflamed. Small amounts appear in saliva, and the fluids of the eye and lung. Tetracyclines appear in the milk of nursing mothers where concentrations may be 60% or more of those in the plasma. They diffuse across the placenta and appear in the foetal circulation in concentrations of about 25 to 75% of those in the maternal blood. Tetracyclines are retained at sites of new bone formation and recent calcification and in developing teeth.
Biotransformation
In the circulation 20-65% of tetracycline is bound to plasma proteins.
The tetracyclines have been classified in terms of their duration of action in the body, although the divisions appear to overlap somewhat.
Elimination
The tetracyclines are excreted in the urine and faeces. Renal clearance is by glomerular filtration. Up to 55% of a dose is eliminated unchanged in the urine; concentrations in the urine of up to 300µg/ml of tetracycline may be reached two hours after a usual dose is taken and be maintained for up to 12 hours. Urinary excretion is increased if urine is alkalinised. The tetracyclines are excreted in the bile where concentrations 5-25 times those in plasma can occur. Since there is some enterohepatic reabsorption complete elimination is slow. Considerable quantities occur in the faeces after administration.5.3 Preclinical safety data
No data of relevance which is additional to that already included in other sections of the SPC.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
Tablet core:
Lactose
Alginic Acid
Pregelatinised Maize Starch
Sodium Laurilsulfate
Talc
Magnesium Stearate
Sodium Starch Glycolate (Type A)
Tablet coating:
Sucrose Talc
Titanium Dioxide E171
Dispersed Yellow 15005 (containing Sunset Yellow E110).6.2 Incompatibilities
Not applicable.6.3 Shelf life
3 years.6.4 Special precautions for storage
Tablet containers: Do not store above 25°C. Keep the container tightly closed.
Blister packs: Do not store above 25°C. Store in the original package.6.5 Nature and contents of container
PP tablet containers with LDPE caps of 28, 100 or 1000 tablets.
PVC/PVdC-Aluminium blister pack (250 micron PVC externally with 40 gsm PVdC, 20 micron hard tempered aluminium) of 28 tablets.6.6 Special precautions for disposal and other handling
No special requirements for disposal.
- Instruction Content
- ## Composition
Each tablet contains Tetracycline Hydrochloride 250.0 mg.
Excipient(s) with known effect-
For the full list of excipients, see section 6.1.
## Pharmaceutical Form
Coated tablet.
Orange, sugar coated tablet with no markings.
## Clinical Particulars
4.1 Therapeutic indications
Tetracycline is a bacteriostatic broad-spectrum antibiotic, active against a wide variety of gram-positive and gram-negative organisms.
Infections caused by tetracycline-sensitive organisms include:
1) Respiratory tract infections: Pneumonia and other lower respiratory tract infections due to susceptible strains of Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae and other organisms. Mycoplasma pneumoniae pneumonia. Treatment of chronic bronchitis (including the prophylaxis of acute exacerbations) and whooping cough.
2) Urinary tract infections: Caused by susceptible strains of the 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. Tetracycline is also indicated in chancroid, granuloma inguinale and lymphogranuloma venereum.
4) Tetracycline is an alternative drug in the treatment of penicillin resistant gonorrhoea and syphilis.
5) Skin infections: Acne vulgaris when antibiotic therapy is considered necessary and severe rosacea.
6) Ophthalmic infections: Trachoma, although the infectious agent, as judged by immunofluorescence, is not always eliminated. Inclusion conjunctivitis may be treated with oral tetracycline alone or in combination with topical agents.
7) Rickettsial infections: Rocky mountain spotted fever, typhus group, Q fever and Coxiella endocarditis and tick fevers.
8) Other infections: Stagnant loop syndrome. Psittacosis, brucellosis (in combination with streptomycin), cholera, bubonic plague, louse and tick-borne relapsing fever, tularaemia, glanders, melioidosis and acute intestinal amoebiasis (as an adjunct to amoebicides).
Tetracycline is an alternative drug in the treatment of leptospirosis, gas-gangrene and tetanus.4.2 Posology and method of administration
\*\*\*Posology\*\*\*
Tetracycline should be given one hour before or two hours after meals, since food and some dairy products interfere with absorption. The tablets should be taken with a good drink of water.Therapy should be continued for up to three days after symptoms have subsided.
All infections due to group a beta-haemolytic streptococci should be treated for at least 10 days.
Adults, the elderly and children over 12 years: The minimum recommended dosage is 250mg every six hours. Therapeutic levels are attained more rapidly by the administration of 500mg initially, followed by 250mg every six hours. For severe infections, the dosage may be increased to 500mg every six hours
Children under 12 years of age: Contraindicated in this age group.
Elderly: Usual adult dose. Caution should be observed as subclinical renal insufficiency may lead to drug accumulation.
Renal impairment: In general tetracyclines are contraindicated in renal impairment and the dosing recommendations only apply if use of this class of drug is deemed absolutely essential. Total dosage should be decreased by reduction of recommended individual doses and/or by extending time intervals between doses.
Dosage recommendations in specific infections:
Skin infections: 250 – 500mg daily in single or divided doses should be administered for at least three months in the treatment of acne vulgaris and severe rosacea.
Brucellosis: 500mg tetracycline four times daily accompanied by streptomycin.
Sexually transmitted diseases: 500mg four times daily for seven days is recommended in the following infections: Uncomplicated gonoccal infections (except anorectal infections in man); uncomplicated urethral, endocervical or rectal infection caused by Chlamydia trachomatis; non-gonoccal urethritis caused by Ureaplasma urealyticum.
Acute epididymo-orchitis caused by Chlamydia trachomatis, or Neisseria gonorrhoea, 500mg four times daily for 10 days. Primary and secondary syphilis: 500mg four times daily for 15 days. Syphilis of more than one year's duration, (latent syphilis of uncertain or more than one year's duration, cardiovascular or late benign syphilis) except neurosyphilis, should be treated with 500mg, four times daily for 30 days.
Patient compliance with this regimen may be difficult so care should be taken to encourage optimal compliance. Close follow-up including laboratory tests, is recommended.
\*\*\*Method of Administration\*\*\*
For oral administration4.3 Contraindications
Known hypersensitivity to any of the tetracyclines or any of the other constituents in the formulation; chronic renal or hepatic dysfunction, renal impairment, particularly if severe, pregnancy, lactation, systemic lupus erythematosus, children under 12 years (see sections 4.4, 4.6 and 4.8) ; pregnancy and breastfeeding women.
Benign intracranial hypertension has been reported following the concomitant use of tetracyclines and Vitamin A or retinoids and therefore concurrent use should be contraindicated (see section 4.5 and 4.8).4.4 Special warnings and precautions for use
Tetracyclines depress plasma prothrombin activity; therefore reduced dosages of concurrent anticoagulants may be required.
The use of tetracyclines if administered during tooth development, in the last half of pregnancy and in children under the age of 12 years may cause permanent tooth discolouration (yellow-grey-brown) (see sections 4.3, 4.6 and 4.8) Enamel hypoplasia has also been reported. This adverse reaction is more common during long-term use of the drug but has been observed following repeated short-term courses.
The use of tetracycline in general is contraindicated in renal impairment due to excessive systemic accumulation and used with caution in patients with hepatic impairment or those receiving drugs which may have hepatotoxic effects; high doses should be avoided. High doses of tetracyclines have been associated with a syndrome involving fatty liver degeneration and pancreatitis. They should not be used with penicillins and they should not be discontinued if supra-infection occurs.
The anti-anabolic action of tetracyclines may cause an increase in BUN. While this is not a problem in those with normal renal function, in patients with significantly impaired renal function, higher serum levels of tetracycline may lead to azotaemia, hyperphosphataemia and acidosis.
In long-term therapy, periodic laboratory evaluation of organ systems, including haemopoietic, renal and hepatic studies should be performed.
Tetracycline is probably porphyrinogenic. Advice of a porphyria specialist should be sought for tetracycline use in patients with acute porphyria.
Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, patients should be warned to avoid direct exposure to natural or artificial sunlight and that treatment should be discontinued at the first evidence of skin erythema or skin discomfort.
SLE (systemic lupus erythematosus) can be exacerbated by the use of tetracyclines.
Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment (including several weeks after treatment) with Tetracycline tablets, may be symptomatic of Clostridium difficile-associated disease (CDAD). CDAD may range in severity from mild to life threatening, the most severe form of which is pseudomembranous colitis (see section 4.8). It is therefore important to consider this diagnosis in patients who develop serious diarrhoea during or after treatment with Tetracycline tablets. If CDAD is suspected or confirmed Tetracycline tablets should be stopped immediately and appropriate therapy initiated without delay. Anti-peristaltic drugs are contraindicated in this clinical situation.
Cross resistance between tetracyclines may develop in micro-organisms and cross- sensitisation patients. The use of antibiotics may occasionally result in the overgrowth of nonsusceptible organisms including Candida (see section 4.8). Constant observation of the patient is essential. Tetracycline should be discontinued and appropriate therapy instituted if there are signs/symptoms of overgrowth of resistant organisms including candida, enteritis, glossitis, stomatitis, vaginitis, pruritis ani or staphylococcal enterocolitis.
Patients with rare hereditary problems of fructose or galactose intolerance, the LAPP lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
When treating venereal disease, where co-existent syphilis is suspected, proper diagnostic procedures should be utilised. In all such cases, monthly serological tests should be made for at least four months.
Care is advised when administered to patients with myasthenia gravis. Tetracycline may increase muscle weakness in patients with myasthenia gravis.
The tablet coating contains Sunset Yellow (E110) which may cause allergic reactions.
Sodium
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.
Sucrose
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.4.5 Interaction with other medicinal products and other forms of interaction
Tetracycline should not be used with penicillins.
Tetracyclines depress plasma prothrombin activity and reduced doses of concomitant anticoagulants such as coumarins and phenindione may be required. Tetracycline may prolong the action of coumarin anticoagulants.
Absorption of tetracycline from the gastrointestinal tract is impaired by the concomitant administration of di and trivalent cations such as iron, calcium, zinc salts, bismuth, magnesium and aluminium salts. Absorption of zinc and oral iron is impaired by tetracycline. Administration of medicinal products containing these cations and tetracycline should be maximally separated by at least two to three hours. The following should be avoided when taking tetracycline: antacids, bismuth containing ulcer-healing drugs, drugs such as quinapril tablets which contain magnesium carbonate and didanosine which contains calcium and magnesium excipients.
Absorption of tetracycline is impaired by food, milk and dairy products, sucralfate, tripotassium dicitratobismuthate and strontium ranelate (manufacturer of strontium ranelate advises avoid concomitant use).
There have been reports of nephrotoxicity (increased blood urea nitrogen and serum creatinine) and death in some cases when tetracycline therapy has been combined with methoxyflurane.
Tetracycline may increase the hypoglycaemic effects of insulin and sulphonylureas in patients with diabetes mellitus.
The absorption of tetracycline may be reduced by the concomitant administration of sucralfate. Separating administration should be considered.
Absorption of tetracycline is possibly reduced by colestipol, colestyramine and antidiarrhoeal preparations such as kaolin-pectin and bismuth subsalicylate
Combination of tetracyclines with diuretics may be detrimental to renal function and may aggravate nephrotoxicity by volume depletion.
Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline in conjunction with penicillin.
Tetracycline may cause an increase in serum lithium levels. Tetracycline may cause an increase in serum digoxin levels.
Tetracycline may cause an increase in the risk of methotrexate toxicity. Regular monitoring of toxicity is necessary when taken concurrently.
Increased risk of ergotism when tetracycline given with ergotamine and methysergide.
A few cases of pregnancy or breakthrough bleeding have been attributed to the concurrent use of tetracycline with oral contraceptives and alternative contraceptive advice should be sought where necessary.
Tetracycline reduces plasma concentration of atovaquone.
There is a possible increased risk of benign intracranial hypertension with tetracyclines and retinoids (acitretin, isotretinoin, tretinoin). Concomitant use should be avoided.
Antibacterials inactivate oral typhoid vaccine. Vaccination should not commence within 3 days after completing treatment with any antibacterial agents. Also, it is preferable that antibacterial therapy should not commence within 3 days after the last dose of vaccine.4.6 Fertility, pregnancy and lactation
\*\*\*Pregnancy\*\*\*
Not to be used in pregnancy unless essential to the patient's welfare. Tetracyclines cross the placenta and may have toxic effects on foetal tissues, particularly on skeletal development (see sections 4.3, 4.4 and 4.8). Tetracycline may be deposited in deciduous and permanent teeth giving permanent discolouration. It should not be used during pregnancy or lactation.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the foetus.
The use of tetracycline compounds during pregnancy has been associated with reports of maternal liver toxicity.
Use in newborns, infants and children: All tetracyclines form a stable calcium complex in any bone-forming tissue.
A decrease in fibula growth rate has been observed in premature infants given oral tetracycline in doses of 25mg/kg every 6 hours. This reaction was reversed when drug was discontinued.
\*\*\*Breast-feeding\*\*\*
Tetracyclines are also excreted in breast milk and are therefore contraindicated in nursing mothers.4.7 Effects on ability to drive and use machines
No significant effect.4.8 Undesirable effects
There are no modern clinical studies available that can be used to determine the frequency of undesirable effects.
The following convention has been utilised for the classification of frequency. Very common ≥ 1/10; common ≥ 1/100 and < 1/10; uncommon ≥ 1/1000 and < 1/100; rare ≥ 1/10,000 and < 1/1000; very rare < 1/10,000; not known (cannot be estimated from the available data).
| | | | | | |
| --- | --- | --- | --- | --- | --- |
| \*\*System Organ Class\*\* | \*\*Common\*\* ≥ \*\*1/100 to < 1/10\*\* | \*\*Uncommon\*\* ≥ \*\*1/1 000 to < 1/100\*\* | \*\*Rare\*\* ≥ \*\*1/10 000 to < 1/1 000\*\* | \*\*Very Rare\*\* \*\*< 1/10 000\*\* | \*\*Frequency not known (cannot be estimated from available data)\*\* |
| \*\*Infections and infestations:\*\* | | | | | As with all antibiotics, overgrowth of resistant organisms (Candida albicans, in particular); this may cause candidiasis, pseudomembranous colitis (\*Clostridium difficile\* overgrowth), glossitis, stomatitis, vaginitis or staphylococcal enterocolitis (caused by resistant staphylococci), rectal and vaginal irritation, inflammatory lesions (with candida overgrowth) in the anogenital regions (see section 4.4) |
| \*\*Blood & lymphatic system disorders\*\* | | | Haemolytic anaemia, thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and eosinophilia | | |
| \*\*Immune system disorders\*\* | | | | | Hypersensitivity reactions including rash, exfoliative dermatitis, Stevens- Johnson syndrome, urticaria, angioedema, toxic epidermal necrolysis, anaphylaxis, anaphylactoid purpura, pericarditis, exacerbation of systemic lupus erythematosus (see sections 4.3 and 4.8), fixed drug eruptions |
| \*\*Endocrine disorders:\*\* | | | | | When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discolouration of the thyroid gland. No abnormalities of thyroid function are known to occur. |
| \*\*Nervous system disorders\*\* | | | | | Headache, dizziness PT Cerebellar syndrome Cerebellar syndrome (eg. ataxia, dysarthria, gait impairment, nystagmus and tremor), which may resolve upon discontinuation of the drug, have been observed with Pylera. |
| \*\*Eye disorders\*\* | | | | | visual disturbances, permanent visual loss |
| \*\*Ear & labyrinth disorders\*\* | | | Impaired hearing | | |
| \*\*Vascular disorders\*\* | | | | | Bulging fontanelles in infants; benign intracranial hypertension in juveniles and adults (see section 4.3). Treatment should cease if evidence of raised intracranial pressure develops, such as severe or persistent headache, dizziness, tinnitus and visual disturbances including blurred vision, scotomata and diplopia. While the condition and related symptoms usually resolve soon after discontinuation of the tetracycline, the possibility of permanent sequelae exists. |
| \*\*Gastrointestinal disorders\*\* | | | Dysphagia. Oesophagitis and oesophageal ulceration (most of these patients took medication immediately before going to bed) have been reported in patients taking oral tetracyclines in solid dose form, usually where medication was taken immediately before retiring for bed or with inadequate fluids. | | Gastrointestinal irritations, nausea, vomiting, diarrhoea, pancreatitis, anorexia, abdominal discomfort, permanent tooth discolouration and enamel hypoplasia in children (see sections 4.3, 4.4 and 4.6). Tooth discolouration has also been seen in adults. If gastric irritation occurs, tablets should be taken with food. |
| \*\*Hepatobiliary disorders:\*\* | | | Transient increases in liver function test values, hepatitis, jaundice, hepatic failure | | Hepatotoxicity associated with fatty liver. |
| \*\*Skin & subcutaneous tissue disorders\*\* | | | Serious skin reactions | | Erythematous and maculo-papular rashes, photosensitivity (patients exposed to direct sunlight or ultraviolet light should be advised to discontinue treatment if any skin reaction occurs), pruritis, bullous dermatoses, skin discolouration |
| \*\*Musculoskeletal, connective tissue & bone disorders\*\* | | | | | Increased muscle weakness in patients with myasthenia gravis (see section 4.4). |
| \*\*Renal & urinary disorders\*\* | | | Acute renal failure, nephritis | | Raised serum urea, renal dysfunction, especially in patients with pre-existing renal impairment |
\*\*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 or search for MHRA Yellow Card in the Google Play or Apple App Store..4.9 Overdose
\*Symptoms:\*
There may be nausea and vomiting.
Crystalluria and haematuria may occur following very large doses.
Hypersensitivity reactions may occur.
\*Treatment:\*
There is no specific antidote.
Gastric decontamination is not necessary.
Give oral fluids for severe vomiting and diarrhoea if required.
Manage anaphylaxis reactions conventionally.
Single brief convulsions do not require treatment. If frequent or prolonged control with intravenous diazepam or lorazepam.
General symptomatic therapy as indicated by the patient's clinical condition.
## Pharmacological Properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antibacterials for systemic use, tetracyclines
ATC code: J01A A07
Mechanism of action
Tetracycline is a broad spectrum antibiotic. It is mainly bacteriostatic and acts by interfering with bacterial protein synthesis.
Tetracyclines are taken up into sensitive bacterial cells by an active transport process. Once within the cell they bind reversibly to the 30S subunit of the ribosome, preventing the binding of aminoacyl transfer RNA and inhibiting protein synthesis and hence cell growth. Although tetracyclines also inhibit protein synthesis in mammalian cells they are not actively taken up, permitting selective effects on the infecting organism.
The deposition of tetracycline in and discolouration of teeth is a problem if given to children or during pregnancy.
Hepatotoxicity may be a problem in patients with impaired liver function.
Susceptibility testing breakpoints
MIC (minimum inhibitory concentration) interpretive criteria for susceptibility testing have been established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for tetracycline and are listed here: https://www.ema.europa.eu/documents/other/minimum-inhibitoryconcentration-mic-breakpoints\\_en.xlsx5.2 Pharmacokinetic properties
Absorption
Most tetracyclines are incompletely absorbed from the gastrointestinal tract, about 60- 80% of a dose of tetracycline usually being available. The degree of absorption is diminished by the presence of divalent and trivalent metal ions with which tetracyclines form stable insoluble complexes and to a variable degree by milk or food. Formulation with phosphate may enhance the absorption of tetracycline.
Plasma concentrations will depend upon the degree of absorption. Administration of tetracycline 500mg every 6 hours generally produces steady-state concentrations of 4- 5µg/ml. Peak plasma concentrations occur about 1-3 hours after ingestion. Higher concentrations can be achieved after intravenous administration; concentrations may be higher in women than in men.
Distribution
They are widely distributed throughout the body tissues and fluids. Concentrations in cerebrospinal fluid are relatively low, but may be raised if the meninges are inflamed. Small amounts appear in saliva, and the fluids of the eye and lung. Tetracyclines appear in the milk of nursing mothers where concentrations may be 60% or more of those in the plasma. They diffuse across the placenta and appear in the foetal circulation in concentrations of about 25 to 75% of those in the maternal blood. Tetracyclines are retained at sites of new bone formation and recent calcification and in developing teeth.
Biotransformation
In the circulation 20-65% of tetracycline is bound to plasma proteins.
The tetracyclines have been classified in terms of their duration of action in the body, although the divisions appear to overlap somewhat.
Elimination
The tetracyclines are excreted in the urine and faeces. Renal clearance is by glomerular filtration. Up to 55% of a dose is eliminated unchanged in the urine; concentrations in the urine of up to 300µg/ml of tetracycline may be reached two hours after a usual dose is taken and be maintained for up to 12 hours. Urinary excretion is increased if urine is alkalinised. The tetracyclines are excreted in the bile where concentrations 5-25 times those in plasma can occur. Since there is some enterohepatic reabsorption complete elimination is slow. Considerable quantities occur in the faeces after administration.5.3 Preclinical safety data
No data of relevance which is additional to that already included in other sections of the SPC.
## Pharmaceutical Particulars
6.1 List of excipients
Tablet core:
Lactose
Alginic Acid
Pregelatinised Maize Starch
Sodium Laurilsulfate
Talc
Magnesium Stearate
Sodium Starch Glycolate (Type A)
Tablet coating:
Sucrose Talc
Titanium Dioxide E171
Dispersed Yellow 15005 (containing Sunset Yellow E110).6.2 Incompatibilities
Not applicable.6.3 Shelf life
3 years.6.4 Special precautions for storage
Tablet containers: Do not store above 25°C. Keep the container tightly closed.
Blister packs: Do not store above 25°C. Store in the original package.6.5 Nature and contents of container
PP tablet containers with LDPE caps of 28, 100 or 1000 tablets.
PVC/PVdC-Aluminium blister pack (250 micron PVC externally with 40 gsm PVdC, 20 micron hard tempered aluminium) of 28 tablets.6.6 Special precautions for disposal and other handling
No special requirements for disposal.
