1 Name of Medicine
Doxycycline hyclate.
2 Qualitative and Quantitative Composition
Doxycycline is a broad spectrum antibiotic synthetically derived from oxytetracycline.
Doxycycline-WGR tablets contain doxycycline 50 mg or 100 mg as doxycycline hyclate.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Doxycycline-WGR 50 mg tablets.
White film-coated circular biconvex tablet having a diameter of 6.3 mm.
Doxycycline-WGR 100 mg tablets.
White film-coated, biconvex tablet, with a breakline on one face.4.1 Therapeutic Indications
Infections caused by the following microorganisms: Mycoplasma pneumoniae (primary atypical pneumonia); Rickettsiae (Queensland tick typhus, epidemic typhus fever, Q fever, murine endemic typhus fever, Australo-Pacific endemic scrub typhus): Chlamydia psittaci (psittacosis); Chlamydia trachomatis (lymphogranuloma venereum, trachoma, inclusion conjunctivitis).
(Doxycycline is indicated in the treatment of trachoma, although the infectious agent is not always eliminated, as judged by immunofluorescence. Inclusion conjunctivitis may be treated with oral doxycycline alone, or in combination with topical agents.)
Borreliae (relapsing fever); Calymmatobacterium (Donovania) granulomatis (granuloma inguinale).
Infections caused by the following Gram-negative microorganisms: Vibrio sp. (cholera); Brucella sp. (Brucellosis; in conjunction with streptomycin); Haemophilus ducreyi (chancroid); Yersinia pestis (plague); Francisella tularensis (tularaemia); Bartonella bacilliformis (Bartonellosis); Bacteroides sp. When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of infections due to: Treponema pallidum (syphilis); Treponema pertenue (yaws); Neisseria gonorrhoea (see Section 4.2 Dose and Method of Administration).
Doxycycline is not the drug of choice in the treatment of any type of staphylococcal infection or infections caused by Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, Enterococcus faecalis or any type of enteric bacteria because many strains of these organisms have been shown to be resistant to doxycycline. Doxycycline should not be used in these infections unless the organism has been shown to be sensitive. For upper respiratory infections due to group A - haemolytic streptococci (including prophylaxis of rheumatic fever), penicillin is the usual drug of choice.
In acute intestinal amoebiasis doxycycline may be a useful adjunct to amoebicides. In severe acne doxycycline may be a useful adjunctive therapy.
Doxycycline is indicated, in adults and children older than 10 years, as chemoprophylaxis for malaria caused by Plasmodium falciparum and, in combination with other antimalarial agents, against malaria caused by Plasmodium vivax. Doxycycline is only able to suppress malaria caused by P. vivax. As there are relatively few locations where P. vivax does not co-exist to some extent with P. falciparum, it is recommended that doxycycline should be used routinely with other agents, for example chloroquine.
Note.
The 50 mg tablet is not a paediatric formulation.4.2 Dose and Method of Administration
Note.
The 50 mg tablet is not a paediatric formulation.
Administration of adequate amounts of fluid with the tablets is recommended to reduce the risk of oesophageal irritation and ulceration. Morning, rather than late night dosing may be preferable. As the recumbent posture may delay oesophageal transit of the tablets, the patient should not lie down for sometime after taking the tablets. To reduce the possibility of gastric irritation, it is recommended that doxycycline be given with food or milk. The absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk. Antacids containing aluminium, calcium or magnesium and preparations containing iron impair absorption and should not be given to patients taking doxycycline.
The usual dosage and frequency of administration of doxycycline differs from that of other tetracyclines. Exceeding the recommended dosage may result in an increased incidence of side effects. Therapy should be continued at least 24 to 48 hours after symptoms and fever have subsided.
Tetracyclines are not the drugs of choice for the treatment of streptococcal infections (see Section 4.1 Therapeutic Indications). However when used, therapy should be continued for 10 days.
Adults and children over 8 years (and above 50 kg in weight).
The usual dose of doxycycline is 200 mg on the first day of treatment (administered as 100 mg every twelve hours) followed by a maintenance dose of 100 mg/day. The maintenance dose may be administered as a single dose or as 50 mg every twelve hours. In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every twelve hours is recommended.
Acute uncomplicated gonococcal infections.
100 mg twice daily for 5 to 7 days.
Resistance of tetracyclines is not uncommon amongst gonococci. The use of tetracycline in the treatment of gonorrhoea should, therefore, be accompanied by monitoring of efficacy.
Primary and secondary syphilis.
300 mg a day in divided doses for at least 10 days.
Louse-borne typhus.
Has been successfully treated with a single oral dose of 100 or 200 mg according to severity.
For the prevention of scrub typhus.
200 mg as a single dose.
For children above 8 years of age without skeletal growth retardation but weighing less than 50 kg.
The adult dose of 100 mg should be recalculated on a weight basis as 2 mg/kg (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
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.
Severe acne.
Some efficacy has been demonstrated in some individuals at a dose of 50 mg/day over a period of 12 weeks. No data showing efficacy beyond 12 weeks have been submitted.
Malaria chemoprophylaxis.
100 mg once a day; commencing two days prior to entering malarious areas, while in the malarious area and for two weeks after leaving the malarious area. A maximum of doxycycline 100 mg daily for 8 weeks is recommended, as safety after 8 weeks has not been clearly established (see Section 5.1 Pharmacodynamic Properties, Mechanism of action, Microbiology; Section 4.1 Therapeutic Indications about combination with other antimalarial agents for prophylaxis against P. vivax).4.3 Contraindications
Hypersensitivity to any of the tetracyclines or any of the excipients. Rare cases of benign intracranial hypertension have been reported after tetracyclines and after vitamin A or oral retinoids such as isotretinoin or etretinate. Concomitant treatment is therefore contraindicated (see Section 4.8 Adverse Effects (Undesirable Effects)).
Use in pregnancy (16 weeks post conception) and lactation. See Section 4.6 Fertility, Pregnancy and Lactation.
The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
4.4 Special Warnings and Precautions for Use
Use with caution in the following circumstances.
The use of antibiotics may occasionally result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, the antibiotic should be discontinued and appropriate therapy instituted.
Venereal disease.
In venereal disease when coexistent syphilis is suspected, proper diagnostic measures including a dark field examination should be done before treatment is started and the blood serology repeated monthly for at least four months.
Oesophageal injury.
If Doxycycline-WGR capsules are ingested in an incorrect manner, there is a risk of adhesion of the capsule to oesophagus. If this happens, oesophageal injury may occur. Dysphagia, retrosternal pain, new or worsening heartburn are possible symptoms of such injury. In order to avoid oesophageal injury, Doxycycline-WGR capsules must be ingested with at least 100 mL of fluid (half a glass) and the patient must remain upright for at least 30 minutes. Administration in the morning is recommended rather than in the evening.
Rarely, oesophagitis and oesophageal ulceration have been reported in patients receiving doxycycline tablets. Most of these patients took medication immediately before going to bed. Administration of adequate amounts of fluid with the tablets is recommended to reduce the risk of oesophageal irritation and ulceration, and late evening ingestion of the dose should be avoided.
To reduce the possibility of gastric irritation, it is recommended that doxycycline be given with food or milk. The absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk.
If doxycycline is used to treat infections due to group A - haemolytic streptococci, treatment should continue for at least 10 days.
Intracranial hypertension.
Intracranial hypertension (IH) has been associated with the use of tetracyclines including doxycycline (see Section 4.3 Contraindications; Section 4.8 Adverse Effects (Undesirable Effects)). The use of tetracyclines in infants, even in the usual therapeutic doses, may cause increased intracranial pressure and bulging of the fontanelles. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Clinical manifestations include headache, blurred vision, diplopia and vision loss. Although intracranial hypertension typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Discontinuation of therapy typically results in prompt return of the pressure to normal. However, since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize.
Antibiotic associated pseudomembranous colitis and CDAD.
Clostridium difficile associated diarrhoea (CDAD) and antibiotic associated pseudomembranous colitis have been reported with nearly all antibacterial agents including doxycycline, and may range 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 and C. difficile produces toxins A and B which contribute to the 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 must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases appropriate therapy with a suitable oral antibacterial agent effective against Clostridium difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated. Drugs which delay peristalsis, e.g. opiates and diphenoxylate with atropine may prolong and/or worsen the condition and should not be used.
Check the following before use.
In long-term therapy, periodic laboratory evaluation of organ systems, including haemopoietic, renal and hepatic studies should be performed.
The use of the drugs of the tetracycline class, including doxycycline, during tooth development (latter 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. Doxycycline, therefore, should not be used in this age group unless other drugs are not likely to be effective or are contraindicated. The use of tetracyclines in infants, even in the usual therapeutic doses, may cause increased intracranial pressure and bulging of the fontanelles. Discontinuation of therapy results in prompt return of the pressure to normal.
Photosensitivity.
Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracycline. 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.
Severe skin reactions.
Severe 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. Fixed drug eruptions have occurred with doxycycline and have been associated with worsening severity upon subsequent administrations, including generalized bullous fixed drug eruption (see Section 4.8 Adverse Effects (Undesirable Effects)). If severe skin reactions occur, discontinue doxycycline immediately and institute appropriate therapy.
Antibiotic associated pseudomembranous colitis has been reported with many antibiotics including doxycycline. A toxin produced with Clostridium difficile appears to be the primary cause. The severity of the colitis may range from mild to life threatening. It is important to consider this diagnosis in patients who develop diarrhoea or colitis in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy). Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases, appropriate therapy such as oral antibacterial agents effective against Clostridium difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated.
Drugs which delay peristalsis, e.g. opiates and diphenoxylate with atropine (Lomotil) may prolong and/or worsen the condition and should not be used.
Use in renal impairment.
The anti-anabolic action of the tetracyclines may cause an increase in serum urea. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function.
Hepatic function.
Abnormal hepatic function has been reported rarely and has been caused by both the oral and parenteral administration of tetracyclines, including doxycycline.
Use in the elderly.
No data available.
Paediatric use.
(See Section 4.4 Special Warnings and Precautions for Use about use during tooth development.)
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 premature infants given oral tetracycline in doses of 25 mg/kg every six hours. This reaction was shown to be reversible when the drug was discontinued.
Effects on laboratory tests.
No data available.4.5 Interactions with Other Medicines and Other Forms of Interactions
Plasma levels of doxycycline are reduced by the ingestion of alcohol or the administration of barbiturates, anticonvulsants (phenytoin, carbamazepine), disodium hydrogen edetate, sodium bicarbonate, sodium lactate and acetazolamide and ethoxzolamide.
Antacids containing aluminium, calcium or magnesium and preparations containing iron impair absorption and should not be given to patients taking doxycycline.
Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines in conjunction with penicillin.
Because the tetracyclines have been shown to depress plasma prothrombin activity, patients on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.
Concurrent use of doxycycline may render oral contraceptives less effective and breakthrough bleeding may occur. Unplanned pregnancy may occur with this combination. A barrier method of contraception should be used while taking doxycycline and for seven days following completion of the course of doxycycline.
The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity.
4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
No data available.
(Category D)
Tetracyclines are safe for use during the first 18 weeks of pregnancy (16 weeks post conception) after which they cause discolouration of the baby's teeth.
During the period of mineralisation of a child's teeth (the second and third trimester of pregnancy, the neonatal period and the first 8 years of life) tetracyclines may induce hypoplasia of the enamel and discolouration of the teeth. Tetracyclines also accumulate in the growing skeleton. These products should be avoided during the second and third trimesters of pregnancy. Large doses of tetracyclines have caused acute fatty necrosis of the liver in pregnant women, especially those with pyelonephritis.
Doxycycline appears in the milk of lactating women. It forms a stable calcium complex in any bone forming tissue and a decrease in the fibula growth rate has been observed in premature infants. The use of drugs of the tetracycline class during tooth development may also cause permanent discolouration of the teeth. Doxycycline should not be given to nursing mothers.4.7 Effects on Ability to Drive and Use Machines
The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.
4.8 Adverse Effects (Undesirable Effects)
Doxycycline is generally well tolerated. Due to doxycycline's virtually complete absorption, side effects of the lower bowel, particularly diarrhoea, have been infrequent. The following adverse effects have been observed in patients receiving doxycycline.
Cases of benign intracranial hypertension have been reported with tetracyclines. It has also occurred with concomitant vitamin A or retinoids such as isotretinoin and etretinate (see Section 4.3 Contraindications).
More common reactions.
Dermatological.
Photosensitive dermatitis, erythematous rash, maculopapular rash, morbilliform rash, pustular rash, urticaria, onycholysis and discolouration of the nails.
Gastrointestinal.
Nausea, anorexia, vomiting, dysphagia, diarrhoea, oesophagitis, oesophageal ulceration, abdominal pain, glossitis, black hairy tongue.
Hypersensitivity.
Urticaria, exacerbation of systemic lupus erythematosus and Jarisch-Herxheimer reaction has been reported in the setting of spirochete infections treated with doxycycline.
Hepatic.
Cholestatic hepatitis, fatty liver degeneration.
Renal.
Dose related increase in serum urea (see Section 4.4 Special Warnings and Precautions for Use).
Musculoskeletal.
Tooth discolouration, enamel hypoplasia.
Others.
Bulging fontanelles have been reported in young infants following full therapeutic dosage. The sign disappeared rapidly when the drug was discontinued.
When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discolouration of thyroid glands. No abnormalities of thyroid function studies are known to occur.
Less common reactions.
Gastrointestinal.
Enterocolitis (see Section 4.4 Special Warnings and Precautions for Use), inflammatory lesions (with monilial overgrowth) in the anogenital region, dyspepsia and pseudomembranous colitis enterocolitis (see Section 4.4 Special Warnings and Precautions for Use), C. difficile diarrhoea. Abnormal hepatic function has been reported rarely (< 1/1000), pancreatitis.
Dermatological.
Exfoliative dermatitis, Stevens-Johnson syndrome, Toxic Epidermal Necrolysis (TEN), erythema multiforme and fixed drug eruption.
Musculoskeletal.
Arthralgia, myalgia.
Genitourinary.
Acute renal failure.
Hypersensitivity.
Angioneurotic oedema, anaphylaxis, anaphylactoid purpura, pericarditis, anaphylactic reaction, serum sickness, hypotension, dyspnoea, peripheral oedema, tachycardia.
Haematological and reticuloendothelial.
Phlebitis associated with intravenous administration; leucopenia, thrombocytopenia, purpura; increase in prothrombin time, haemolytic anaemia, eosinophilia.
Nervous system.
Malaise, flushing, headache, confusion, taste loss, stupor, hypoesthesia, paraesthesia, somnolence, benign intracranial hypertension in adults, increased intracranial pressure in infants. In relation to benign intracranial hypertension, symptoms included blurring of vision, scotomata and diplopia. Permanent visual loss has been reported.
Ocular.
Conjunctivitis, periorbital oedema.
Hearing/vestibular.
Tinnitus.
Psychiatric.
Depression, anxiety, hallucination.
Respiratory.
Bronchospasm.
Rare reactions.
Retrosternal pain.
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.4.9 Overdose
The symptoms of overdosage may be an exaggeration of the gastro-intestinal side effects, the main ones being nausea, vomiting and diarrhoea. High doses of tetracyclines have been shown to cause an increase in serum urea so after a large overdosage a medical examination is advised.
Treatment of overdosage should be symptomatic and supportive.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Mechanism of action.
Microbiology. Doxycycline is primarily bacteriostatic and is thought to exert its anti-microbial effect by the inhibition of protein synthesis. It is active against a wide range of Gram-positive and Gram-negative organisms (see Section 4.1 Therapeutic Indications).
Disc susceptibility test.
Dilution or diffusion techniques - either quantitative (MIC) or breakpoint, should be used following a regularly updated, recognised and standardized method (e.g. Clinical and Laboratory Standards Institute [CLSI formerly NCCLS]). Standardised susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.
A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable.
A report of "Intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small-uncontrolled technical factors from causing major discrepancies in interpretation.
A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Note.
The prevalence of resistance may vary geographically for selected species and local information on resistance is desirable, particularly when treating severe infections.
Clinical trials.
No data available.
5.2 Pharmacokinetic Properties
Absorption.
Tetracyclines are readily absorbed though to a varying extent. They are concentrated by the liver in the bile, and excreted in the urine and faeces at high concentrations and in a biologically active form. Doxycycline is virtually completely absorbed after oral administration. Its absorption is not significantly affected by the presence of food or milk.
Distribution.
Following a 300 mg dose, the mean peak serum concentration of doxycycline in normal adult volunteers was 6.3 microgram/mL and the medium time to peak concentration was 2.7 hours. The mean serum level 24 hours after dosing was 1.8 microgram/mL.
Normalised to a 200 mg dose, the mean peak serum concentration of doxycycline was about 4.3 microgram/mL.
Metabolism.
The metabolism of doxycycline in the human body has not been investigated. In vitro serum protein binding of doxycycline varies from 23 to 93%.
Haemodialysis does not alter serum half-life.
Excretion.
Excretion of doxycycline by the kidney is about 40% in 72 hours in individuals with normal function (creatinine clearance above 75 mL/minute).
This percentage excretion may fall as low as 1 to 5% in 72 hours in individuals with severe renal insufficiency (creatinine clearance below 10 mL/minute). Studies have shown no significant difference in serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function.
The fraction of drug that is not eliminated with urine is mainly excreted in the faeces. More than 90 percent of an oral dose of doxycycline is eliminated from the body within 72 hours of drug administration.
5.3 Preclinical Safety Data
Genotoxicity.
No data available.
Carcinogenicity.
No data available.6 Pharmaceutical Particulars
6.1 List of Excipients
Doxycycline-WGR 100 mg and Doxycycline-WGR 50 mg tablets also contain: microcrystalline cellulose, maize starch, colloidal anhydrous silica, magnesium stearate and Opadry complete film coating system Y-1R-7000B white.
6.2 Incompatibilities
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store below 30°C. Protect from light and moisture.
6.5 Nature and Contents of Container
Doxycycline-WGR 100 mg tablets.
Available in PVC/PVDC/Al blister packs of 7 or 21 tablets.
Doxycycline-WGR 50 mg tablets.
Available in PVC/PVDC/Al blister packs of 25 tablets.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.
6.7 Physicochemical Properties
Chemical name: 6-deoxy-5-oxytetracycline. It is a light yellow crystalline powder which has a high lipid solubility and a low affinity for calcium binding. It is highly stable in normal human serum. It will not degrade into an epianhydro form.
Chemical structure.
Chemical name: Hydrochloride hemiethanolate hemihydrate of (4S,4aR,5S,5aR,6R,12aS)-4-(dimethylamino)- 3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene- 2-carboxamide.
Molecular formula: C22H25ClN2O8. Molecular weight: 512.9.
CAS number.
[24390-14-5].7 Medicine Schedule (Poisons Standard)
Schedule 4 (Prescription only medicine).
Summary Table of Changes
