Consumer medicine information

APO-Doxycycline Tablets

Doxycycline

BRAND INFORMATION

Brand name

APO-Doxycycline

Active ingredient

Doxycycline

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Doxycycline Tablets.

What is in this leaflet

This leaflet answers some common questions about doxycycline. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may want to read it again.

What this medicine is used for

Doxycycline is used to:

  • treat certain types of infections
  • control acne
  • prevent some forms of malaria.

Doxycycline belongs to a group of medicines called tetracycline antibiotics.

How it works

Doxycycline works by killing or stopping the growth of bacteria which cause infections or make acne worse. It also works against parasites that cause malaria. It will not work against infections caused by viruses such as colds or the flu.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

This medicine is available only with a doctor's prescription.

This medicine is not addictive.

This medicine should not be given to children 8 years of age or under for infections, or to children 10 years of age or under for preventing malaria.

Doxycycline, like other tetracyclines, may cause enamel loss and staining in developing teeth or increase the pressure on your child's brain.

Before you take this medicine

When you must not take it

Do not take this medicine if you have an allergy to:

  • doxycycline
  • other tetracyclines
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin

Do not take this medicine if you are taking methoxyflurane or oral retinoid medicines such as vitamin A, isotretinoin or etretinate.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • liver disease
  • systemic lupus erythematosus (a disease affecting the skin, joints and kidneys).

Tell your doctor if you work outdoors, or you are exposed to direct sunlight or ultra-violet light. Doxycycline may cause your skin to become more sensitive to UV or sunlight, resulting in severe sunburn.

Tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. This medicine should not be taken during the last half of pregnancy.

Doxycycline, like other tetracyclines, may cause enamel loss and staining in developing teeth or increase the pressure on your child's brain. High doses of tetracyclines may also cause liver problems in pregnant women.

Doxycycline should not be used in breastfeeding women.

If you have not told your doctor about any of the above, tell them before you start taking this medicine.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you get from your pharmacy, supermarket or health food shop.

Some medicines may interact with doxycycline. These include:

  • oral retinoid medicines such as preparations containing vitamin A, isotretinoin or etretinate.
    You must not take doxycycline with these medicines.
  • warfarin and other medicines used to prevent blood clots.
  • penicillin antibiotics
  • barbiturates (e.g. phenobarbitone)
  • medicines used to treat seizures (e.g. phenytoin, carbamazepine)
  • methoxyflurane, an anaesthetic
  • acetazolamide and ethoxzolamide, used to help the body get rid of salt and water
  • disodium hydrogen edetate
  • sodium bicarbonate, found in indigestion remedies
  • sodium lactate
  • the contraceptive pill (birth control pill). Doxycycline may decrease the effectiveness of some birth control pills. Your doctor may advise you to use an additional method of contraception while taking doxycycline.

If you are taking any of these, you may need a different dose, or you may need to take different medicines.

Some medicines may interfere with the absorption of doxycycline into the body. Do not take any of the following medicines whilst taking doxycycline:

  • medicines for indigestion (e.g. calcium, magnesium or aluminium salts found in antacids, or bismuth salts)
  • preparations that contain iron including vitamin preparations.
  • other preparations containing calcium, magnesium or aluminium

In addition, alcohol can reduce the blood levels of doxycycline and should be avoided.

Other medicines not listed above may also interact with doxycycline.

How to take this medicine

Follow carefully all directions given to you by your doctor. They may differ to the information contained in this leaflet.

How much to take

Your doctor will tell you how much of this medicine you should take, depending on your condition, age, body weight and whether you are taking any other medicines.

For treating infections

The usual dose is 100 mg twice a day for the first day, followed by 100 mg once a day thereafter.

For acne:

The usual dose is 50 mg once a day.

For the prevention of malaria:

The usual dose is 100 mg once a day, commencing two days before entering the malarious area, during the visit, and for four weeks after leaving the area. You should ensure that you take your medicine with unfailing regularity for the whole time you are there and after leaving the malarious area, as parasites may still emerge from the liver for up to four weeks after the last possible exposure to infection.

Travel medicine advice may change from time to time and it is best to ask your doctor or pharmacist for the most up to date information about which antimalarial medicines are suitable for certain areas, and for how long you need to take the medicine after leaving the malarious area.

How to take it

Swallow the tablets whole with a full glass of water or milk while sitting or standing upright.

Do not crush or chew the tablets.

Do not lie down immediately after swallowing doxycycline. It is important to stay upright, for example sitting, standing or walking around for at least half an hour after swallowing your tablet. This is to help avoid irritation to your food pipe, also called the oesophagus.

When to take it

Take your medicine during or immediately after a meal, at about the same each day (preferably in the morning). If you take it on an empty stomach, it may cause stomach upset.

Avoid taking doxycycline at bedtime.

How long to take it for

Keep taking this medicine for as long as your doctor has told you, even if you begin to feel better after a few days. If you do not complete the full course prescribed by your doctor, the infection may not clear completely, or your symptoms may return.

For treating infections, doxycycline is normally taken for one to two weeks.

For controlling acne, doxycycline 50 mg daily is normally taken over a period of twelve weeks.

For preventing malaria, doxycycline 100 mg daily is normally taken for up to eight weeks.

Your doctor may prescribe doxycycline for longer periods.

Make sure you have enough to last over weekends and holidays.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose at the usual time.

Otherwise take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for missed doses. This may increase the chance of you experiencing side effects.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to the Emergency Department at your nearest hospital if you think that you or anyone else may have taken too much of this medicine. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention. If you take too much doxycycline, you may feel sick or be sick.

While you are taking this medicine

Things you must do

If you are taking doxycycline for an infection and your symptoms do not improve within a few days or they become worse, tell your doctor.

If you get severe diarrhoea tell your doctor immediately. Do this even if it occurs several weeks after you have stopped taking this medicine. Diarrhoea may mean that you have a serious condition affecting your bowel. You may need urgent medical attention.

Do not take any diarrhoea medicine without first checking with your doctor.

If you are about to be started on any new medicine, tell your doctor that you are taking this medicine.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

Tell your doctor if you are about to have any blood tests.

Keep all your doctor’s appointments. Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects.

Things you must not do

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not take your medicine to treat any other complaint unless your doctor tells you to.

Do not stop taking your medicine, or change the dosage, without first checking with your doctor. If you do not complete the full course, all the bacteria causing your infection may not be killed. These bacteria may continue to grow and multiply so that your infection may not clear completely, or it may return.

Things to be careful of

Protect your skin when you are in the sun, especially between 10am and 3pm. Do not use a sunlamp while taking doxycycline. Doxycycline may cause your skin to be much more sensitive to sunlight than it is normally. Exposure to sunlight may cause a skin rash, itching, redness, or a severe sunburn.

If outdoors, wear protective clothing and use a 30+ sunscreen.

If your skin appears to be burning, tell your doctor as soon as possible.

Be careful driving or operating machinery until you know how doxycycline affects you.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking doxycycline.

All medicines can have side effects. Sometimes they are serious but most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Tell your doctor if you notice any of the following:

  • oral thrush - white, furry, sore tongue and mouth
  • vaginal thrush - sore and itchy vagina and/or discharge
  • nail changes (i.e. change in colour or loosening from the nail bed)
  • stomach upsets, such as pain, indigestion, or feeling sick
  • loss of appetite or taste sensation
  • sore mouth or tongue
  • mild irritation of the oesophagus (food pipe)
  • difficulty or pain when swallowing
  • tooth discolouration, changes in tooth enamel

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Emergency department at your nearest hospital:

  • shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin (signs of an allergic reaction)
  • increased pressure in the brain (headache, blurred vision, vomiting)
  • severe diarrhoea, stomach pain often associated with nausea and vomiting (pancreatitis)
  • severe sunburn
  • flaking of the skin
  • dizziness
  • more frequent bruising than normal
  • passing less urine than normal
  • yellowing of the skin or eyes, pale stools, dark urine (jaundice)
  • a rare, potentially life-threatening, drug-induced sensitivity reaction that includes skin rashes, blood changes, fever and dysfunction of internal organs
  • a reaction that can happen after starting doxycycline therapy for a particular bacterial infection (spirochete infections, e.g. Lyme disease); symptoms include fever, chills, muscle pain and worsening of skin rash.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor immediately if you notice any of the following side effects, particularly if they occur several weeks after you have finished taking doxycycline:

  • severe stomach cramps
  • watery and severe diarrhoea, which may be bloody
  • fever, in combination with one or both above.

These are serious side effects that may need urgent medical attention. Doxycycline can cause some bacteria that are normally harmless and present in the bowel to multiply and cause the above symptoms.

Do not take any diarrhoea medicine without first checking with your doctor. Other side effects not listed above may occur in some patients.

Storage and disposal

Storage

Keep your medicine in its pack until it is time to take it. If you take your medicine out of its pack it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C. Protect it from light.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine left over.

Product description

What it looks like

50 mg tablets: Dull yellow, round biconvex tablets.

Blister packs of 25. AUST R 78597

100 mg tablets: Dull yellow, round, biplane tablets with a single sided scored notch.

Blister packs of 7 & 21. AUST R 78598

*Not all strengths and/or pack sizes may be available.

Ingredients

Each tablet contains either 50 mg or 100 mg of doxycycline monohydrate as the active ingredient.

It also contains the following:

  • microcrystalline cellulose
  • sodium starch glycollate
  • hydrogenated castor oil
  • povidone
  • colloidal anhydrous silica magnesium stearate.

This medicine does not contain gluten, lactose, sucrose, tartrazine or any other azo dyes.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

APO is a registered trade mark of Apotex Pty Ltd.

This leaflet was prepared in September 2020

Published by MIMS November 2020

BRAND INFORMATION

Brand name

APO-Doxycycline

Active ingredient

Doxycycline

Schedule

S4

 

1 Name of Medicine

Doxycycline monohydrate.

2 Qualitative and Quantitative Composition

Each tablet contains 50 mg or 100 mg of doxycycline (as monohydrate), as the active ingredient.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

50 mg tablets.

Dull yellow, round, biconvex tablets.

100 mg tablets.

Dull yellow, round, biplane tablets with a single sided score notch.

4 Clinical Particulars

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, or in combination with topical agents.);
Calymmatobacterium (Donovania) granulomatis (granuloma inguinale).
And the following Gram-negative micro-organisms:
Vibrio species (cholera);
Brucella species (brucellosis (in conjunction with streptomycin));
Yersinia pestis (plague);
Francisella tularensis (tularemia);
Bartonella bacilliformis (bartonellosis);
Bacteroides species.
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).

Note.

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, Streptococcus 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 tract infections due to group A beta-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.

4.2 Dose and Method of Administration

APO-Doxycycline Tablets are intended for oral administration.

Dosage.

Administration of adequate amounts (at least 100 mL) 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 some time (at least 30 minutes) 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 ten days.

Adults and children over 8 years (and ≥ 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. A 50 mg dose can be delivered using half of one 100 mg tablet or one whole 50 mg tablet. 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 five to seven days.
Resistance to tetracyclines is not uncommon amongst gonococci. The use of tetracyclines in the treatment of gonorrhoea should, therefore, be accompanied by monitoring of efficacy.

Primary and secondary syphilis.

300 mg/day in divided doses for at least ten days.

Louse-borne typhus.

This has been successfully treated with a single oral dose of 100 mg or 200 mg according to severity.

Prevention of scrub typhus.

200 mg as a single dose.

Children over 8 years (and < 50 kg without skeletal growth).

The adult dose of 100 mg should be calculated on a weight basis of 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 four weeks after leaving the malarious area. A maximum of 100 mg daily for eight weeks is recommended, as safety after eight weeks has not been clearly established (see Section 5 Pharmacological Properties; 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 of doxycycline tablets.
Use in pregnancy (16 weeks post conception) and use in lactation are contraindicated (see Section 4.6 Fertility, Pregnancy and Lactation).
Rare cases of benign intracranial hypertension have been reported after tetracyclines and oral retinoids such as isotretinoin or etretinate and Vitamin A. Concomitant treatment is therefore contraindicated (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
The concurrent use of tetracyclines 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

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.

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 stabilise.

Photosensitivity.

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. 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 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.

Use in hepatic impairment.

Abnormal hepatic function has been reported rarely and has been caused by both the oral and parenteral administration of tetracyclines, including doxycycline.

Gastrointestinal disease.

History of colitis.

Antibiotics should be prescribed with care for individuals with a history of gastrointestinal disease, especially ulcerative colitis, regional enteritis or antibiotic associated colitis.

Pseudomembranous colitis.

Clostridium difficile associated diarrhoea (CDAD) and antibiotic associated pseudomembranous colitis have been reported with nearly all antibiotics 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.

Concomitant diseases.

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.

Long term use.

In long term therapy, periodic laboratory evaluation of organ systems, including haemopoietic, renal and hepatic studies should be performed.
If doxycycline is used to treat infections due to group A beta-haemolytic streptococci, treatment should continue for at least 10 days.

Oesophagitis.

Rarely, oesophagitis and oesophageal ulceration have been reported in patients receiving doxycycline tablets. Most of these patients took medication immediately before going to bed. Patients should be instructed to take doxycycline with plenty of water (at least 100 mL), remain upright and not take their treatment before going to bed. Withdrawal of doxycycline and investigation of oesophageal disease should be considered if symptoms such as new or worsening dyspepsia, dysphagia or retrosternal pain occur. Caution is required in the treatment of patients with known oesophageal reflux disorders.
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.

Use in the elderly.

No data available.

Paediatric use.

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.
Tetracyclines also interfere with tooth development (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy). 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 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. Therefore doxycycline should not be used in children younger than 8 years of age 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.

Effects on laboratory test.

False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Anticoagulants.

There have been reports of prolonged prothrombin time in patients taking warfarin and doxycycline. Because the tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.

Antacids.

Antacids containing aluminium, calcium or magnesium, or other drugs containing these cations, bismuth salts and preparations containing iron impair absorption and should not be given to patients taking doxycycline.

Antibiotics.

Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline in conjunction with penicillin.

Oral contraceptives.

Concurrent use of tetracyclines 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.

Methoxyflurane.

The concurrent use of tetracyclines and methoxyflurane has been reported to result in fatal renal toxicity.

Other.

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, acetazolamide and ethoxzolamide.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category D)
(See Section 4.3 Contraindications).
Tetracyclines are safe for use during the first 18 weeks of pregnancy, after which they cause discolouration of the baby's teeth.
During the period of mineralisation of a child's teeth (the last half 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 latter half of pregnancy.
There are no adequate and well-controlled studies on the use of doxycycline in pregnant women. The vast majority of reported experience with doxycycline during human pregnancy is short-term, first trimester exposure. An expert review of published data on experiences with doxycycline use during pregnancy by TERIS - the Teratogen Information System - concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no risk. A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. Sixty-three (0.19%) of the controls and fifty six (0.30%) of the cases were treated with doxycycline. This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (i.e. in the second and third months of gestation) with the exception of a marginal relationship with neural tube defect based on only two exposed cases.
A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10 days with doxycycline during early first trimester. All mothers reported their exposed infants were normal at 1 year of age.
Results in animal studies indicate that tetracyclines cross the placenta, are found in foetal tissues and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy.
Large doses of tetracyclines have caused acute fatty necrosis of the liver in pregnant women, especially those with pyelonephritis. Large doses of the medicine should not be used in pregnant women, or those likely to become pregnant.
 (See Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
Tetracyclines are excreted in human milk, however, the extent of absorption of tetracyclines, including doxycycline, by the breastfed infant is not known. Short-term use by lactating women is not necessarily contraindicated; however, the effects of prolonged exposure to doxycycline in breast milk are unknown. Because of the potential for serious adverse reactions in breastfed infants from doxycycline, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of the drug to the mother.
Doxycycline is present in the milk of lactating women. It forms a stable calcium complex in bone-forming tissue and a decrease in the fibula growth has been observed in prematures. The use of medicines 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.
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).
Due to its 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.

More common effects.

Dermatological.

Photosensitive skin reactions (see Section 4.4 Special Warnings and Precautions for Use), photosensitive dermatitis, erythematous rash, maculopapular rash, morbilliform rash, pustular rash, urticaria, photo-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.

Nervous system disorders.

Dizziness.

Other.

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 effects.

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 (see Section 4.4 Special Warnings and Precautions for Use), C. difficile diarrhoea, hepatotoxicity, hepatitis. Abnormal hepatic function has been reported rarely (< 1/1000), pancreatitis.

Dermatological.

Exfoliative dermatitis, Stevens-Johnson syndrome, Toxic Epidermal Necrolysis (TEN).

Musculoskeletal.

Arthralgia, myalgia.

Genitourinary.

Acute renal failure.

Hypersensitivity.

Angioneurotic oedema, anaphylaxis, anaphylactic shock, anaphylactic reaction, anaphylactoid purpura, pericarditis, serum sickness, hypotension, dyspnoea, peripheral oedema, tachycardia, erythema multiforme, drug rash with eosinophilia and systemic symptoms (DRESS).

Haematological and reticuloendothelial.

Phlebitis associated with intravenous administration; leucopenia; thrombocytopenia purpura; increase in prothrombin time; haemolytic anaemia, eosinophilia, neutropenia.

Nervous system.

Flushing, malaise; headache, confusion; taste loss; stupor; hypoaesthesia; 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.

Hepatic.

Hepatotoxicity.

Rare reactions.

Dysphagia, 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 and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Symptoms.

Tetracyclines, including doxycycline, generally have low toxicity. Severe toxicity following acute overdosage is unlikely, with nausea and vomiting being the most common effects after ingestion of therapeutic and overdose amounts.

Treatment.

Treatment may include immediate discontinuation of medication, dilution with water or milk and general supportive care. Antacids may be useful in managing gastric irritation. In most cases, gastrointestinal decontamination is not required. Plasma levels are not clinically useful and specific laboratory monitoring is not needed unless otherwise indicated.
In case of an oral overdose with doxycycline, gastric lavage should be considered to remove unabsorbed portions of the substance. Remaining residues of doxycycline should be minimised by administering antacids or calcium or magnesium salt in order to produce non-absorbable chelates.
Doxycycline is not sufficiently dialysable. Thus, haemodialysis or peritoneal dialysis is not very effective. In massive overdose, there is a risk of liver damage sometimes accompanied by pancreatitis.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Doxycycline is a broad spectrum antibiotic synthetically derived from oxytetracycline.

Microbiology.

Doxycycline is primarily bacteriostatic and is thought to exert its antimicrobial effect through inhibition of protein synthesis. It is active against a wide range of Gram-positive and Gram-negative organisms.

Susceptibility testing.

The drugs in the tetracycline class have closely similar antimicrobial spectra, and cross resistance among them is common. Micro-organisms may be considered susceptible if the MIC (minimum inhibitory concentration) is less than 1.0 microgram/mL and intermediate if the MIC is 1.0 to 5.0 microgram/mL.

Disc susceptibility plate testing.

A tetracycline disc may be used to determine microbial susceptibility to drugs in the tetracycline class. If the Kirby-Bauer method of disc susceptibility testing is used, a 30 microgram tetracycline disc should give a zone of at least 19 mm when tested against a tetracycline-susceptible bacterial strain.
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 the alternative, clinically feasible drugs, the tests 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 reached 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

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.

Absorption.

Doxycycline is virtually completely absorbed after oral administration. Its absorption is not significantly affected by the presence of food or milk.

Distribution.

Following a 200 mg dose, normal adult volunteers averaged peak serum levels of 2.6 microgram/mL of doxycycline at 2 hours decreasing to 1.45 microgram/mL at 24 hours. There is limited diffusion of doxycycline into cerebrospinal fluid after oral administration.

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%.

Excretion.

Excretion of doxycycline by the kidney is about 40% in 72 hours in individuals with normal renal 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% of an oral dose of doxycycline is eliminated from the body within 72 hours of drug administration.
Haemodialysis does not alter serum half-life.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, sodium starch glycollate, hydrogenated castor oil, povidone, colloidal anhydrous silica and magnesium stearate.

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 25°C. Protect from light.

6.5 Nature and Contents of Container

50 mg tablets.

Blister pack (PP/Al) of 25 tablets. (AUST R 78597).

100 mg tablets.

Blister packs (PP/Al) of 7 and 21 tablets. (AUST R 78598).
APO and APOTEX are registered trade marks of Apotex Pty. Ltd.
Not all strengths and/or pack sizes may be available.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Doxycycline is a broad-spectrum antibiotic synthetically derived from oxytetracycline. The chemical designation of this light-yellow crystalline powder is 6-deoxy-5-oxytetracycline. Doxycycline 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: 4S, 4aR,5S,5aR,6R,12aS-4- dimethylamino- 1,4,4a,5,5a,6,11,12a- octahydro-3,5,10,12,12a-pentahydroxy- 6-methyl-1,11- dioxonaphthacene-2-carboxamide monohydrate.
Molecular Weight: 462.5.

CAS number.

17086-28-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes