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DOXYCLIN (CAPSULES)

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

DOXYCLIN (CAPSULES)

COMPOSITION:
Each capsule contains: Doxycycline Hydrochloride 115 mg (equivalent to 100 mg Doxycycline).

PHARMACOLOGICAL CLASSIFICATION:
A 20.1.1 Broad and Medium Spectrum Antibiotics

PHARMACOLOGICAL ACTION:
Doxyclin (Doxycycline) exhibits the following distinct advantages over other tetracycline compounds:
1.        The almost complete oral absorption and prolonged half-life results in the therapeutic efficacy of small clinical doses, when administered only once daily. This rapid absorption in the intestinal wall, and wide-spread diffusion in the tissues, is due to the considerable liposolubility and lipophilicity possessed by Doxyclin (Doxycycline). Multiple dose studies have demonstrated that there is a cumulative effect with increments in blood levels on each successive day of administration. The absorption is not significantly impaired by the administration of food and milk.
CLINICAL STUDIES: One third of the normal dose of tetracycline (100 mg) of Doxyclin (Doxycycline) gives peak plasma levels of 1,78 mg/mL after 2 hours, this being greater than the minimum capable of inhibiting most bacterial strains. This level is maintained for at least 24 hours, thus permitting single daily doses of Doxyclin which are lower than other tetracyclines. The 4 hour peak with demethylchlortetracycline (DMTC) is 1,99 mg/mL and DMTC has a plasma half-life of 12,7 hours compared to 15,1 hours with doxycycline.
The relative high plasma levels and prolonged half-life may be due to the lower renal clearance of doxycycline (15,95 mL/min compared to 36,49 mL/min with DMTC). The decrease in renal clearance is not from a decrease in the quantity filtered by the glomeruli, but from a higher tubular resorption; resulting in an exceptionally high concentration in the renal parenchyma.
Comparison of some characteristics of the different tetracyclines. The values concerning doxycycline are taken from the work of Fabre, Filton & Kunz, those concerning the other tetracyclines from Kunin, Dornbush & Finland (2) and Kunin & Finland (3). DC = doxycycline, TC = Tetracycline, OCT = oxytetracycline, CTC = chlortetracycline, DMTC = demethylchlortetracycline.

		DC	TC	OTC	CTC	DMCT
Dose studied	mg	200	500	500	500	250
Concentration in the serum after 24 hours	pg/mL	1,45	0,7	0,5	0,3	0,6
Half-life in the serum	hr	22,2	8,2	9,2	5,6	11,8
Rate of decline	% per hr	3,1	8,2	7,6	12,4	5,5
Serum protein-binding	%	25-31	20-28	23-42	42-54	34-48
Urinary excretion in 24 hours	%	23	48	58	16	31
Urinary excretion in 72 hours	%	39	59	69	18	43
Urinary Clearance	mL/min	22-33	73	98	32	35

Excretion of Doxyclin (doxycycline) is effected almost entirely in 3 days time by 3 different mechanisms - approximately 40% leaves in the urine, about 5% in the stools, and the rest (approximately 50%) is transformed in the body and bowel into bacteriologically inactive derivatives.
2.        Doxyclin (doxycycline) has a greater activity against a variety of organisms (particularly Staphylococci and Enterococci) than other tetracyclines. As the inhibiting minimum concentration is lower, the dosage required to obtain active minimum tetracycline levels is considerably lower. The lower therapeutic doses and higher host tissue content give excellent tolerance with a minimum of toxic effects. The increased anti-bacterial effect is due to the markedly high, early and sustained blood levels achieved, the tissue concentrations being 5-10 times higher than other tetracyclines. Doxyclin (doxycycline) thus remains in the blood for longer periods and passes early into the tissues bringing an intense and wide spread anti-bacterial effect.
3.        Doxyclin (doxycycline) exhibits few side effects, mainly nausea which is transient and disappears on continued administration.

INDICATIONS:
Doxyclin (doxycycline) is effective in the treatment of infections due to a large number of gram-positive and gram-negative pathogenic bacteria, and in particular respiratory tract infections - single and multilobe pneumonia and bronchopneumonia due to susceptible strains of Pneumococcus, Streptococcus, Staphylococcus, H-influenzae and Klebsiella pneumoniae. Pharyngitis, tonsillitis, otitis media, bronchitis and sinusitis caused by susceptible strains of B-haemolytic Streptococcus, Staphylococcus, Pneumococcus and H-influenza.
SOFT TISSUE INFECTIONS: Impetigo furunculosis, cellulitis, abscesses, infected wounds, acne, infected traumatic and post-operative wounds caused by susceptible strains of Staphylococcus aureus and albus, Streptococcus, E-coli and Klebsiella Aerobacter organisms.
OPHTHALMIC INFECTIONS: Due to susceptible strains of Gonococci, Staphylococci and H-influenzae.
GASTROINTESTINAL INFECTIONS: Due to susceptible strains of such organisms as E-histolytica, pathogenic E-coli and species of Shigella and Salmonella.
GENITO-URINARY INFECTIONS: Pyelonephritis, cystitis, urethritis, acute gonococcal anterior urethritis, caused by susceptible strains of the Klebsiella Aerobacter group, E-coli, Enterococcus, Staphylococcus, Streptococcus and Neisseria gonorrhoeae.
INFECTIONS: Due to susceptible strains of Bacteroides, Pasteurella, Brucella (with streptomycin), psittacosis, Listeriae, Rickettsia, Mycoplasma pneumoniae, H-pertussis, B-anthracis, C-welchii, N-meningitidis, spirochetes, Donovania granulomatis and prostatitis and trigonitis due to Proteus of Pseucomonas.

CONTRA-INDICATIONS:
Doxyclin (doxycycline) as with other tetracyclines is contra-indicated in individuals who have shown hypersensitivity to it. Reactions due to allergy or individual idiosyncrasy, including phototoxicity, are extremely rare. Patients with a history of photosensitivity reactions should be instructed to avoid exposure to direct sunlight during therapy. Treatment should be discontinued if adverse reactions occur.

WARNING:
If renal impairment exists, even usual doses may lead to excessive systemic accumulation of the drug and possible liver toxicity. Under these conditions lower than usual doses are indicated and if therapy is prolonged doxycycline serum level determination should be performed.

DOSAGE AND DIRECTIONS FOR USE:
Adults and adolescents –200 mg on the first day of treatment (1 capsule every 12 hours). Thereafter 100 mg (1 capsule) daily until disappearance of symptoms. In severe infections 100 mg (1 capsule) every 12 hours is recommended.
For acute gonococcal anterior urethritis in males, a single dose of 300 mg or 100 mg twice a day is indicated. In the female, gonococcal infections should be treated with doses of 100 mg twice a day until cure is effected.
In streptococcal infections, continue therapy for 10 days to prevent the development of rheumatic fever of glomerulonephritis. If gastric irritation occurs, Doxyclin (doxycycline) should be administered with food or milk, as the absorption of doxycycline, unlike other tetracyclines, is not markedly affected by simultaneous ingestion.
The absorption of doxycycline is decreased with simultaneous administration of aluminium hydroxide gel.

SIDE EFFECTS AND SPECIAL PRECAUTIONS:
As with other antibiotics, side effects, mostly due to modification of the gastro-intestinal or local microbial flora, have been reported but are rare due to the low dosage of Doxyclin (doxycycline). These include glossitis, stomatitis, proctitis, nausea, diarrhoea, vomiting, onycholysis, and nail discolouration, vaginitis and dermatitis. Allergic reactions such as dermatitis, urticaria and anaphylaxis are rare.
While tetracyclines may form a stable calcium complex in any bone forming tissue, doxycycline binds calcium less strongly than other tetracyclines. However, the use of Doxyclin (doxycycline) during both development (last trimester of pregnancy, neonatal period or early childhood) may cause discolouration of the teeth (yellowish-grey-brownish). This effect occurs mainly during the long-term use but has been occasionally observed in usual short treatment courses.
Increased intracranial pressure with bulging fontanelles has been observed with infants receiving therapeutic doses of tetracycline. The mechanism of this phenomenon is unknown and signs and symptoms have disappeared rapidly on cessation of treatment with no sequelae.
Where lesions of primary or secondary syphilis are suspected during treatment of gonorrhoea, proper diagnostic procedures (including dark field examination) should be performed. Monthly serological tests should be made for at least 4 months.
As with other tetracyclines, elevation of CGOT and CGPT values or elevated BUN have been reported. Anaemia, neutropenia and eosinophilia have also been reported.

IDENTIFICATION:
A hard gelatine capsule (Size 3) with an opaque light blue cap and an opaque medium orange body containing an homogenous mustard yellow powder.

PRESENTATION:
Containers of 5, 50 and 100 capsules.

STORAGE INSTRUCTIONS:
Store below 25°C, in a tightly closed container protected from light and moisture.
KEEP OUT OF THE REACH OF CHILDREN.

REGISTRATION NUMBER:
E/20.1.1/26

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Pharmacare Limited, 7 Fairclough Road, PORT ELIZABETH 6001

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
9 March 1984.

        G434A
        KOHLER C&P P.E.
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