Product Information
Doxycycline Sandoz 50 mg/100 mg Tablets
February 2016
Page 1
PRODUCT INFORMATION
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DOXYCYCLINE
SANDOZ
50
AND
100
TABLETS
NAME OF THE MEDICINE
Doxycycline monohydrate
(4S,4aR,5S,5aR,6R,12aS)-4-(Dimethylamino)-3,5,10,12,12a-pentahydroxy-6-methyl1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide monohydrate
OH
O
OH
O
O
OH
C
NH2
* H2O
OH
H
H
CH3 H
H
OH H
N(CH3)2
CAS: 17086-28-1
Empirical formula: C22H24N2O8.H20
MW: 462.5
DESCRIPTION
Doxycycline 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.
Doxycycline is
oxytetracycline.
a
broad
spectrum
antibiotic
synthetically
derived
from
Excipients – microcrystalline cellulose, sodium starch glycollate type A,
hydrogenated castor oil, povidone, colloidal anhydrous silica and magnesium stearate.
PHARMACOLOGY
Pharmacodynamics
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 (see INDICATIONS).
Strains of Bacillus anthracis isolated from the environment are generally sensitive to
doxycycline. Because of the potential for laboratory manipulation of B. anthracis, in
the treatment of anthrax, clinical isolates should be tested for antibiotic susceptibility
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by validated test methods. Therapy should be modified in light of antimicrobial
susceptibility testing results.
Susceptibility testing. Medicines in the tetracycline class have closely similar
antimicrobial spectra, and cross resistance among them is common. Microorganisms
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.
A tetracycline disc may be used to determine microbial susceptibility to medicines in
the tetracycline class. If the Kirby-Bauer method of disc susceptibility is used, a 30
microgram tetracycline disc should give a zone of at least 19 mm when tested against
a tetracycline susceptible bacterial strain.
Disc susceptibility testing. Dilution or diffusion techniques – either quantitative
(MIC) or breakpoint, should be used following a regularly updated, recognized and
standardised method (e.g. 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 the alternative, clinically feasibile
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.
Pharmacokinetics
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. Following a 200 mg dose, normal adult volunteers averaged peak serum levels
of 2.6 g/mL of doxycycline at 2 hours decreasing to 1.45 g/mL at 24 hours.
There is limited diffusion of doxycycline into CSF after oral administration.
The metabolism of doxycycline in the human body has not been investigated. In vitro
serum protein binding of doxycycline varies from 23 to 93%.
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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% of an oral dose of doxycycline is eliminated from the body within 72
hours of drug administration.
Haemodialysis does not alter serum half-life.
INDICATIONS
Infections caused by the following micro-organisms: 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.)
Borreliae (relapsing fever);
(granuloma inguinale).
Calymmatobacterium
(Donovania)
granulomatis
Doxycycline Sandoz is indicated for the treatment of Anthrax due to Bacillus
anthracis, including inhalational anthrax (post-exposure) to reduce the incidence or
progression of disease following exposure to aerosolized Bacillus anthracis (see
DOSAGE AND ADMINISTRATION).
Infections caused by the following Gram-negative micro-organisms: Vibrio sp.
(cholera); Brucella sp. (brucellosis; in conjunction with streptomycin); Yersinia pestis
(plague); Francisella tularensis (tularaemia); Bartonella bacilliformis (bartonellosis);
Bacteroides sp.
When penicillin is contraindicated, doxycycline is an alternative medicine in the
treatment of infections due to: Treponema pallidum (syphilis); Treponema pertenue
(yaws); Neisseria gonorrhoea (see DOSAGE AND ADMINISTRATION).
Note: Doxycycline Sandoz is not the medicine 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 Sandoz should not be used in these infections
unless the organism has been shown to be sensitive. For upper respiratory infections
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due to group A beta-haemolytic streptococci (including prophylaxis of rheumatic
fever), penicillin is the usual medicine of choice.
In acute intestinal amoebiasis Doxycycline Sandoz 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 Plasmodium vivax. As there
are relatively few locations where P.vivax does not coexist to some extent with P.
falciparum, it is recommended that doxycycline should be used routinely with other
agents, for example chloroquine.
CONTRAINDICATIONS
Hypersensitivity to doxycycline, any of the excipients in Doxycycline Sandoz or to
any of the tetracyclines. 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.
PRECAUTIONS
Use with caution under the following circumstances
The use of antibiotics may occasionally result in overgrowth of nonsusceptible
organisms, including fungi. If superinfection occurs, the antibiotic should be
discontinued and appropriate therapy instituted.
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
medicines and treatment should be discontinued at the first evidence of skin erythema.
Use in patients with renal impairment
The antianabolic 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.
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.
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Long term treatment
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.
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
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 medicine
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. Medicines which delay peristalsis, e.g. opiates and diphenoxylate with
atropine may prolong and/or worsen the condition and should not be used.
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 disorder should be
considered if symptoms such as dyspepsia 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.
Bacillus anthracis infection
In the treatment of severe disease due to Bacillus anthracis initial IV therapy is
recommended. Doxycycline should not be used as a single agent for treatment of
severe disease due to Bacillus anthracis, including meningitis. Doxycycline may be
less effective in anthrax meningitis due to poor CNS penetration.
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Use in patients with hepatic impairment
Abnormal hepatic function has been reported rarely and has been caused by both the
oral and parenteral administration of tetracyclines, including doxycycline.
Use in pregnancy (Category D)
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 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
ten 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 foetus (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.
Use in lactation
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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 breastfeeding infants from doxycycline, a
decision should be made whether to discontinue breastfeeding or to discontinue the
medicine, taking into account the importance of the medicine to the mother.
Paediatric use
As with other tetracyclines, doxycycline forms a stable calcium complex in any boneforming 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 effect was
shown to be reversible when the medicine was discontinued.
Tetracyclines also interfere with tooth development (see PRECAUTIONS, Use in
pregnancy). The use of the medicines of the tetracycline class, including Doxycycline
Sandoz, during tooth development (latter half of pregnancy, infancy and childhood to
the age of 8 years) may cause permanent discolouration of the teeth (yellow-greybrown). This effect is more common during long term use of the medicines 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 medicines 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.
INTERACTIONS WITH OTHER MEDICINES
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 containing aluminium, calcium or magnesium or other medicines containing
these cations, bismuth salts, and preparations containing iron impair absorption and
should not be given to patients taking doxycycline.
Since bacteriostatic medicines may interfere with the bactericidal action of penicillin,
it is advisable to avoid giving tetracycline in conjunction with penicillin.
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.
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There are anecdotal reports that concurrent use of tetracyclines may render oral
contraceptives less effective.
The concurrent use of tetracyclines and methoxyflurane has been reported to result in
fatal renal toxicity.
Effects on laboratory tests
False elevations of urinary catecholamine levels may occur due to interference with
the fluorescence test.
ADVERSE EFFECTS
Doxycycline is generally well tolerated. 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 PRECAUTIONS), erythematous
rash, maculopapular rash, morbilliform rash, pustular rash, urticaria, photoonycholysis 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.
Hepatic. Cholestatic hepatitis, fatty liver degeneration.
Renal. Dose related increase in serum urea (see PRECAUTIONS).
Musculoskeletal. Tooth discolouration, enamel hypoplasia.
Others. Bulging fontanelles have been reported in young infants following full
therapeutic dosage. The sign disappeared rapidly when the medicine 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 PRECAUTIONS), inflammatory lesions (with
monilial overgrowth) in the ano-genital region; dyspepsia and pseudomembranous
colitis (see PRECAUTIONS); C. difficile diarrhoea, hepatotoxicity, hepatitis.
Abnormal hepatic function has been reported rarely (< 1/1,000).
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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; thrombocytopenic 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.
DOSAGE AND ADMINISTRATION
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 some time 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
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incidence of side effects. Therapy should be continued at least 24 to 48 hours after
symptoms and fever have subsided.
Tetracyclines are not the medicines of choice for the treatment of streptococcal
infections (see INDICATIONS). However, when used, therapy should be continued
for ten days.
Adults, children over 8 years (and > 50 kg): The usual dose of doxycycline is
200mg 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 five to seven
days.
Resistance to 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 syphiIis. 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
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 retardation): The adult
dose of 100 mg should be recalculated on a weight basis as 2 mg/kg (see
PRECAUTIONS, Use in children).
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
50mg/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 malaria area and for two 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 PHARMACOLOGY,
and INDICATIONS section about combination with other antimalarial agents for
prophylaxis against P. vivax).
Anthrax due to Bacillus anthracis including inhalational anthrax (post-exposure).
Adults. The recommended dose for adults is 100 mg every 12 hours.
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Children 8 years or younger and children weighing 45 kg and less. The recommended
dose is 2.2 mg/kg every 12 hours.
Duration of treatment. It is recommended that treatment be continued for at least 60
days.
Therapy should be modified in light of antimicrobial susceptibility testing results.
OVERDOSAGE
Contact the Poisons Information Centre on 13 11 26 for advice on management of
overdose.
Tetracyclines, including doxycycline, generally have low toxicity.
Symptoms
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 minimized by administering antacids or calcium- or magnesium salt in
order to produce non-absorbable chelates.
Doxycycline is not sufficiently dialyzable. Thus, hemodialysis or peritoneal dialysis is
not very effective.
In massive overdose, there is a risk of liver damage sometimes accompanied by
pancreatits.
PRESENTATION AND STORAGE CONDITIONS
Doxycycline Sandoz 50 mg tablets – dull yellow, round, biconvex.
Available in blister packs of 25 tablets.
Doxycycline Sandoz 100 mg tablets – dull yellow, round, biplane with a single-sided
score notch.
Available in blister packs of 7 tablets.
Store below 25°C.
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Protect from light.
NAME AND ADDRESS OF THE SPONSOR
Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Australia
Tel: 1800 634 500
POISON SCHEDULE OF THE MEDICINE
Schedule 4 – Prescription Only Medicine
Date of first inclusion in the Australian Register of Therapeutic Goods (the
ARTG): 08/10/1998
Date of most recent amendment: 10/02/2016
Sandoz Pty Ltd
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