PHYSICAL AND PHARMACEUTICAL PROPERTIES
Synonyms: Dossiciclina Iclato; Doxycycline Hyclate (BANM, rINNM); Doxycyclini Hyclas.
Chemical Name: Doxycycline hydrochloride hemiethanolate hemihydrate. Molecular Formula: C(22)H(24)N(2)O(8),HCl,1/2C(2)H -(5)OH, -1/2H(2)O Molecular Weight: 512.9 A yellow hygroscopic crystalline powder. Doxycycline hydrochloride 115 mg is approximately equivalent to 100 mg of doxycycline. Ph. Eur. solubilities are: freely soluble in water and in methyl alcohol; sparingly soluble in alcohol; practically insoluble in ether; dissolves in solutions of alkali hydroxides and carbonates. USP solubilities are: soluble in water; slightly soluble in alcohol; practically insoluble in chloroform and in ether; soluble in solutions of alkali hydroxides and carbonates. A 1% solution in water has a pH of 2 to 3. Store in airtight containers. Protect from light. Incompatibilities. Preparations of doxycycline hydrochloride have an acid pH and incompatibility may reasonably be expected with alkaline preparations or with drugs unstable at low pH. Reduced antimicrobial activity has been reported in vitro when doxycycline hydrochloride was mixed with riboflavine.
ADVERSE EFFECTS AND PRECAUTIONS
As for Tetracycline Hydrochloride. Gastrointestinal disturbances are reported to be less frequent than with tetracycline and doxycycline may also cause less tooth discoloration.
Oesophageal ulceration may be a particular problem if capsules or tablets are taken with insufficient fluid or in a recumbent posture: doxycycline should be taken with at least half a glass of water, in an upright position, and one hour or more before retiring to bed. There is some evidence from studies in animals that preparations of the base, which have a higher pH, cause less oesophageal damage than those of the more acid hydrochloride. Dispersible tablets or liquid formulations should be used in elderly patients, who may be at greater risk of oesophageal injury.
Unlike many tetracycline’s, doxycycline does not appear to accumulate in patients with impaired renal function, and aggravation of renal impairment may be less likely.
Anosmia or dysosmia (absent or impaired sense of smell) have occasionally been reported in patients receiving doxycycline, although the association has not been definitely established.
For the suggestion that doxycycline might be porphyrinogenic.
As for Tetracycline Hydrochloride. Doxycycline has a lower affinity for binding with calcium than many tetracycline’s. In consequence its absorption is less likely to be affected by milk or food, although it is still affected by antacids and iron preparations. The metabolism of doxycycline may be accelerated by drugs that induce hepatic enzymes such as alcohol (chronic use); antiepileptics including carbamazepine, phenobarbitone, and phenytoin; and rifampicin. It has been suggested that doxycycline could increase cyclosporin concentrations, but evidence for this seems to be scant.
As for Tetracycline Hydrochloride, Doxycycline is more active than tetracycline against many bacterial species including the enterococci and various anaerobes. Cross-resistance is common although some tetracycline-resistant Staphylococcus aureus respond to doxycycline. Doxycycline is also reported to be more active against protozoa, particularly Plasmodium spp.
For the general pharmacokinetics of the tetracycline’s, see Tetracycline Hydrochloride.
Doxycycline hydrochloride is readily and almost completely absorbed from the gastrointestinal tract and absorption is not significantly affected by the presence of food in the stomach or duodenum. Mean peak plasma concentrations of 2.6 micrograms per mL have been reported 2 hours after a 200-mg dose by mouth, falling to 1.45 micrograms per mL at 24 hours. After intravenous infusion of the same dose peak plasma concentrations are briefly somewhat higher, but become very similar to those after oral administration following equilibration into the tissues.
From 80 to 95% of doxycycline in the circulation is reported to be bound to plasma proteins. Its biological half-life varies from about 12 to 24 hours. Doxycycline is more lipid-soluble than tetracycline. It is widely distributed in body tissues and fluids.
In patients with normal renal function about 40% of a dose is slowly excreted in the urine although more is excreted by this route if urine is made alkaline. However, the majority of a dose of doxycycline is excreted in the faeces following chelation in the intestines. Although doxycycline has been reported to undergo some inactivation in the liver, some sources consider this doubtful; however, the kinetics of doxycycline have been reportedly altered in patients receiving drugs which induce hepatic metabolism.
Doxycycline is stated not to accumulate significantly in patients with renal impairment although excretion in the urine is reduced; increased amounts of doxycycline are excreted in the faeces in these patients. Nevertheless there have been reports of some accumulation in renal failure. Removal of doxycycline by haemodialysis is insignificant.
Concentrations of doxycycline in CSF of patients with neurological manifestations of Lyme disease receiving doxycycline 200 mg daily by mouth ranged from 0.4 to 2.5 micrograms per mL at 4 hours after a dose. (1) This represented 3 to 36% of the serum concentration at that time and was reported to be adequate for the treatment of the infection
USES AND ADMINISTRATION
Doxycycline is a tetracycline derivative with uses similar to those of tetracycline. It may sometimes be preferred to other tetracycline’s in the treatment of sensitive infections because of its fairly reliable absorption and its long half-life which permits less frequent (often once daily) dosage. It also has the advantage that it can be given (with care) to patients with renal insufficiency. However, relatively high doses may need to be given for urinary-tract infections because of its low renal excretion. Doxycycline is normally administered by mouth as doxycycline or its various derivatives. Doses are expressed in terms of doxycycline. The usual dose is 200 mg of doxycycline on the first day (as a single dose or 100 mg repeated after 12 hours), followed by 100 mg daily. Older children weighing 45 kg or less may be given 4 mg per kg body-weight initially and thereafter 2 mg per kg daily but the effect of tetracycline’s on teeth and bones should be considered. In severe infections the initial dosage is maintained throughout the course of treatment. In patients with sensitive gonococcal infections doxycycline has occasionally been given in a single dose of 300 mg, alone or followed by a second similar dose one hour later. For syphilis, doxycycline 200 or 300 mg is given daily for at least 15 or 10 days, respectively. In the treatment of acne a dose of 50 mg daily may be adequate. For relapsing fever and louse-borne typhus, doxycycline 100 or 200 mg may be given as a single dose. For prophylaxis of scrub typhus, 200 mg may be taken as a single dose.
Doxycycline capsules and tablets should be given with plenty of fluid, with the patient in an upright position, and well before retiring for the night. It may be given with food or milk if gastric irritation occurs. Dispersible tablets or liquid formulations are advisable in elderly patients.
In patients in whom oral therapy is not feasible doxycycline may be given, as the hydrochloride, by slow intravenous infusion of a solution containing 0.1 to 1 mg per mL, in doses equivalent to those by mouth. Infusions should be given over 1 to 4 hours.
Doxycycline is used in some areas for the treatment of chloroquine-resistant falciparum malaria in a dose of 200 mg daily for at least 7 days in combination with quinine. Doxycycline 100 mg daily has been used for prophylaxis in areas of high risk where other drugs are likely to be ineffective, but it is not suitable for extended prophylactic use.
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