Not applicable.
None known
Not applicable.
None stated
Not applicable.
The carcinogenic potential of doxycycline has been investigated and no changes indicative of a direct carcinogenic effect were seen. Increases in benign tumours of the mammary gland (fibroadenoma), uterus (polyp) and thyroid (C-cell adenoma), which are consistent with a hormonal effect, were observed in treated females. Doxycycline has shown no mutagenic activity and no convincing evidence of clastogenic activity.
Effects on fertility and reproductive performance and on pre- and post-natal toxicity have been assessed in rats over the dose range 50 to 500 mg/kg/day. At 50 mg/kg/day (88 times the human dose) there was a decrease in the straight-line velocity of sperm, but there was no apparent effect on male or female fertility or on sperm morphology. Maternal toxicity at 500 mg/kg/day was shown by noisy breathing, loose faeces, and transient reductions in both body weight gain and food consumption after parturition with a slight increase in the duration of gestation. No maternal toxicity was apparent at or below 100 mg/kg/day and there was no effect on the F1 generation at 50 mg/kg/day during parturition, lactation or post-weaning. Developmental toxicity studies have not been conducted, but doxycycline is known to cross the placenta.
Hyperpigmentation of the thyroid following administration of members of the tetracycline class has been observed in rats, minipigs, dogs and monkeys and thyroid hyperplasia has occurred in rats, dogs, chickens and mice.
The anticipated human dose for doxycycline, 20 mg b.i.d. is equivalent to ~0.5 mg/kg/day for a 70 kg man. At this dose plasma Cmax and AUC0-24 were 780 ng/ml and 10954 ng*h/ml respectively.
Toxicity following repeated oral administration has been evaluated in rats and cynomolgus monkeys. Discolouration of the thyroid was a finding common to rats exposed at 25 mg/kg/day for 13 weeks or 20 mg/kg/day for 26 weeks, and to cynomolgus monkeys at 30 mg/kg/day for 1 year. Cmax and AUC0-24 following a single oral dose of 25 mg/kg were 2.2 and 1.6 times respectively the values recorded in man. Dose-related increases in both the incidence and severity of tubular degeneration/regeneration in the kidney were seen following administration to cynomolgus monkeys for 28 days or 52 weeks. At 5 mg/kg/day, focal lesions were present after 28 days, but no lesions were present in monkeys treated for 52 weeks. Mean plasma Cmax and AUC0-24 values at 28 days in monkeys receiving 5 mg/kg/day were 1235 ng/ml and 11600 ng*h/ml respectively and there was no evidence of accumulation.
In humans the use of tetracyclines during tooth development may cause permanent discolouration of the teeth (yellow-grey-brown). This reaction is more common during long-term use of the drug but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. As for other tetracyclines, doxycycline forms a stable calcium complex in any bone-forming tissue. A decrease in the fibula growth has been observed in premature infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued.
Pharmacotherapeutic group: Tetracyclines, ATC code: J01 AA02.
Doxyderm is primarily bacteriostatic and is believed to exert its antimicrobial effect by the inhibition of protein synthesis. Doxyderm is active against a wide range of Gram-positive and Gram-negative bacteria and certain other micro-organisms.
Pharmacotherapeutic group: Tetracyclines, ATC code: J01 AA02
Doxyderm is primarily bacteriostatic and is believed to exert its antimicrobial effect by the inhibition of protein synthesis. Doxyderm is active against a wide range of Gram-positive and Gram-negative bacteria and certain other micro-organisms.
Pharmacotherapeutic group: Tetracyclines
ATC code: J01A A02
The active ingredient of Doxyderm, doxycycline, is synthetically derived from oxytetracycline, with a molecular formula of C22H24N2O8-HCl-½ C2H5OH-½ H2O.
Doxyderm is an inhibitor of collagenase activity. Studies have shown that at the proposed 20 mg b.i.d. dose level, Doxyderm reduces the elevated collagenase activity in the gingival crevicular fluid of patients with chronic adult periodontitis, whilst not demonstrating any clinical evidence of anti-microbial activity.
Susceptibility
The dosage achieved with this product during administration is well below the concentration required to inhibit microorganisms commonly associated with adult periodontitis. Clinical studies with this product demonstrated no effect on total anaerobic and facultative bacteria in plaque samples from patients administered this dose regimen for 9 to 18 months. This product SHOULD NOT be used for reducing the numbers of, or eliminating, those microorganisms associated with periodontitis.
Tetracyclines are readily absorbed and are bound to plasma proteins in varying degrees. 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. Studies reported to date indicate that the absorption of doxycycline, unlike certain other tetracyclines, is not notably influenced by the ingestion of food or milk. Following a 200 mg dose, normal adult volunteers averaged peak serum levels of 2.6 micrograms/ml of doxycycline at 2 hours decreasing to 1.45 micrograms/ml at 24 hours. Doxycycline has a high degree of lipid solubility and a low affinity for calcium. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form.
Absorption
Tetracyclines are readily absorbed and are bound to proteins in varying degrees. They are concentrated by the liver in the bile and excreted in the urine and faeces at high concentration and in a biologically active form. Doxyderm is virtually completely absorbed after oral administration. Studies reported to date indicate that the absorption of Doxyderm unlike certain other tetracyclines, is not notably influenced by the ingestion of food or milk.
Following a 200mg dose, normal adult volunteers averaged peak serum levels of 2.6 micrograms/ml at 2hours decreasing to 1.45micrograms/ml at 24 hours. Doxyderm has a high degree of lipid solubility and a low affinity for calcium. It is highly stable in normal human serum. Doxyderm will not degrade into an epianhydro form.
AbsorptionFollowing administration of a single dose of Doxyderm MPC under fasting conditions, the AUCinf and Cmax were 26.7 mcg-h/mL and 1.6 mcg/mL, respectively. The Tmax was 2.8 hours. In a single-dose study to evaluate the relative bioavailability in healthy adult subjects under fasted conditions, Doxyderm MPC 120 mg Tablets were found to be bioequivalent to Doxyderm 100 mg Tablets. When a single dose of Doxyderm MPC 120 mg Tablet was administered with a standardized high-fat high-calorie meal, (937kcal consisting of approximately 55% fat, 30% carbohydrate and 15% protein), the Cmax was approximately 30% lower, but there was no significant difference in the AUCinf compared to administration under fasting conditions.
ExcretionTetracyclines are concentrated in bile by the liver and excreted in the urine and feces at high concentrations and in a biologically active form. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with a creatinine clearance of about 75 mL/min. This percentage may fall as low as 1-5%/72 hours in individuals with a creatinine clearance below 10 mL/min.
Studies have shown no significant difference in the serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter the serum half-life.
Absorption:
Doxycycline is almost completely absorbed after oral administration. Following ingestion of 20 mg doxycycline twice daily, mean maximum plasma concentrations were 0.79 µg/ml. Peak levels were generally achieved 2 hours after administration. Food intake reduced the extent of absorption by 10% and decreased and delayed the peak plasma levels.
Distribution:
Doxycycline is greater than 90% bound to plasma proteins and has an apparent volume of distribution of 50L.
Metabolism:
Major metabolic pathways of doxycycline have not been identified, however, enzyme inducers decrease the half-life of doxycycline.
Elimination:
Doxycycline is excreted in the urine and faeces as unchanged drug. Between 40% and 60% of an administered dose can be accounted for in the urine by 92 hours, and approximately 30% in the faeces. The terminal half-life after a single 20 mg doxycycline dose averaged 18h.
Special populations:
The half-life is not significantly altered in patients with severely impaired renal function. Doxycycline is not eliminated to any great extent during haemodialysis.
No special requirements.
