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Doxycycline

The Elephant Formulary
© 2003-06 Susan K. Mikota DVM and Donald C. Plumb, Pharm.D.
Published by Elephant Care International -
www.elephantcare.org


Elephant specific information, if available, is in blue.

Chemistry - A semi-synthetic tetracycline that is derived from oxytetracycline, doxycycline is available as hyclate, calcium and monohydrate salts. The hyclate salt is used in the injectable dosage form and in oral tablets and capsules. It occurs as a yellow, crystalline powder that is soluble in water and slightly soluble in alcohol. After reconstitution with sterile water, the hyclate injection has a pH of 1.8-3.3. Doxycycline hyclate may also be known as doxycycline hydrochloride.

 

The monohydrate salt is found in the oral powder for reconstitution. It occurs as a yellow, crystalline powder that is very slightly soluble in water and sparingly soluble in alcohol. The calcium salt is formed in situ during manufacturing. It is found in the commercially available oral syrup.

 

Storage/Stability/Compatibility - Doxycycline hyclate tablets and capsules should be stored in tight, light resistant containers at temperatures less than 30°C, and preferably at room temperature (15-30°C). After reconstituting with water, the monohydrate oral suspension is stable for 14 days when stored at room temperature.

 

The hyclate injection when reconstituted with a suitable diluent (e.g., D5W, Ringer’s in­jection, Sodium Chloride 0.9%, or Plasma-Lyte 56 in D5W) to a concentration of 0.1 to 1 mg/ml may be stored for 72 hours if refrigerated. Frozen reconstituted solutions (10 mg/ml in sterile water) are stable for at least 8 weeks if kept at -20°C, but should not be refrozen once thawed. If solutions are stored at room temperature, different manufacturers give dif­ferent recommendations regarding stability, ranging from 12-48 hours. Infusions should generally be completed within 12 hours of administration.

 

Doxycycline hyclate for injection is reportedly compatible with the following IV infusion solutions and drugs: D5W, Ringer’s injection, sodium chloride 0.9%, or Plasma-Lyte 56 in D5W, Plasma-Lyte 148 in D5W, Normosol M in D5W, Normosol R in D5W, invert sugar 10%, acyclovir sodium, hydromorphone HCl, magnesium sulfate, meperidine HCl, morphine sulfate, perphenazine and ranitidine HCl. Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used. It is suggested to consult specialized references for more specific information (e.g., Handbook on Injectable Drugs by Trissel; see bibliography).

 

Pharmacology - Tetracyclines generally act as bacteriostatic antibiotics and inhibit protein synthesis by reversibly binding to 30S ribosomal subunits of susceptible organisms, thereby preventing binding to those ribosomes of aminoacyl transfer-RNA. Tetracyclines also are believed to reversibly bind to 50S ribosomes and additionally alter cytoplasmic membrane permeability in susceptible organisms. In high concentrations, tetracyclines can also inhibit protein synthesis by mammalian cells.

 

As a class, the tetracyclines have activity against most mycoplasma, spirochetes (including the Lyme disease organism), Chlamydia and Rickettsia. Against gram positive bacteria, the tetracyclines have activity against some strains of staphylococcus and strep­tococci, but resistance of these organisms is increasing. Gram positive bacteria that are usually covered by tetracyclines, include Actinomyces sp., Bacillus anthracis, Clostridium perfringens and tetani, Listeria monocytogenes and Nocardia. Among gram negative bac­teria that tetracyclines usually have in vitro and in vivo activity against, include Bordetella sp., Brucella, Bartonella, Haemophilus sp., Pasturella multocida, Shigella, and Yersinia pestis. Many or most strains of E. coli, Klebsiella, Bacteroides, Enterobacter, Proteus and Pseudomonas aeruginosa are resistant to the tetracyclines.

 

Doxycycline generally has very similar activity as other tetracyclines against susceptible organisms, but some strains of bacteria may be more susceptible to doxycycline or minocycline and additional in vitro testing may be required.

 

Uses/Indications - Although there are no veterinary-approved doxycycline products available, its favorable pharmacokinetic parameters (longer half-life, higher CNS penetration) when compared to either tetracycline HCl or oxytetracycline HCl make it a reasonable choice to use in small animals when a tetracycline is indicated, particularly when a tetracycline is indicated in an azotemic patient. Because there is apparently less clinical experi­ence with this agent in small animals than with either tetracycline or oxytetracycline, some caution should be employed before routinely using.

 

In avian species, some clinicians feel that doxycycline is the drug of choice in the oral treatment of psittacosis, particularly when treating only a few birds.

 

Pharmacokinetics - Doxycycline is well absorbed after oral administration. Bioavailability is 90-100% in humans. No bioavailability data was located for veterinary species, but it is thought that the drug is also readily absorbed in monogastric animals. Unlike tetracycline HCl or oxytetracycline, doxycycline absorption may only be reduced by 20% by either food or dairy products in the gut. This is not considered to be clinically important.

 

Tetracyclines as a class, are widely distributed to the heart, kidney, lungs, muscle, pleural fluid, bronchial secretions, sputum, bile, saliva, synovial fluid, ascitic fluid, and aqueous and vitreous humor. Doxycycline is more lipid soluble and penetrates body tissues and fluids better than tetracycline HCl or oxytetracycline, including to the CSF, prostate and eye. While CSF levels are generally insufficient to treat most bacterial infections, doxycycline has been shown to be efficacious in the treatment of the CNS effects associated with Lyme disease in humans. The volume of distribution at steady-state in dogs is approximately 1.5 L/kg. Doxycycline is bound to plasma proteins in varying amounts dependent upon species. The drug is approximately 25-93% bound to plasma proteins in humans, 75-86% in dogs, and about 93% in cattle and pigs.

 

Doxycycline’s elimination from the body is relatively unique. The drug is primarily excreted into the feces via non-biliary routes in an inactive form. It is thought that the drug is partially inactivated in the intestine by chelate formation and then excreted into the intestinal lumen. In dogs, about 75% of a given dose is handled in this manner. Renal excretion of doxycycline can only account for about 25% of a dose in dogs, and biliary excretion less than 5%. The serum half-life of doxycycline in dogs is approximately 10-12 hours and a clearance of about 1.7 ml/kg/min. In calves, the drug has similar pharmacokinetic values. Doxycycline does not accumulate in patients with renal dysfunction.

 

Contraindications/Precautions/Reproductive Safety - Doxycycline is contraindicated in patients hypersensitive to it. Because tetracyclines can retard fetal skeletal development and discolor deciduous teeth, they should only be used in the last half of pregnancy when the benefits outweigh the fetal risks. Doxycycline is considered to be less likely to cause these abnormalities than other more water soluble tetracyclines (e.g., tetracycline, oxyte­tracycline). Unlike either oxytetracycline or tetracycline, doxycycline can be used in patients with renal insufficiency.

 

Until further studies documenting the safety of intravenous doxycycline in horses are done, the parenteral route of administering this drug in horses should be considered con­traindicated.

 

Adverse Effects/Warnings - The most commonly reported sided effects of oral doxycycline therapy in dogs and cats are nausea and vomiting. To alleviate these effects, the drug could be given with food without clinically significant reductions in drug absorption.

 

Tetracycline therapy (especially long-term) may result in overgrowth (superinfections) of non-susceptible bacteria or fungi.

 

In humans, doxycycline (or other tetracyclines) has also been associated with photosensitivity reactions and, rarely, hepatotoxicity or blood dyscrasias.

 

Intravenous injection of even relatively low doses of doxycycline has been associated with cardiac arrhythmias, collapse and death in horses.

 

Overdosage/Acute Toxicity - With the exception of intravenous dosing in horses (see above), doxycycline is apparently quite safe in most mild overdose situations. Oral over­doses would most likely be associated with GI disturbances (vomiting, anorexia, and/or diarrhea). Although doxycycline is less vulnerable to chelation with cations than other tetracyclines, oral administration of divalent or trivalent cation antacids may bind some of the drug and reduce GI distress. Should the patient develop severe emesis or diarrhea, fluids and electrolytes should be monitored and replaced if necessary.

 

Rapid intravenous injection of doxycycline has induced transient collapse and cardiac arrhythmias in several species, presumably due to chelation with intravascular calcium ions. If overdose quantities are inadvertently administered, these effects may be more pronounced.

 

Drug Interactions - When orally administered, tetracyclines can chelate divalent or trivalent cations which can decrease the absorption of the tetracycline or the other drug if it contains these cations. Oral antacids, saline cathartics or other GI products containing aluminum, calcium, magnesium, zinc or bismuth cations are most commonly associated with this interaction. Doxycycline has a relatively low affinity for calcium ions, but it is recommended that all oral tetracyclines be given at least 1-2 hours before or after the cation-containing product.

Oral iron products are also associated with decreased tetracycline absorption, and administration of iron salts should preferably be given 3 hours before or 2 hours after the tetracycline dose. Oral sodium bicarbonate, kaolin, pectin, or bismuth subsalicylate may impair tetracycline absorption when given together orally. Bacteriostatic drugs like the tetracyclines, may interfere with bactericidal activity of the penicillins, cephalosporins, and aminoglycosides. There is some amount of controversy regarding the actual clinical significance of this interaction, however. Tetracyclines may increase the bioavailability of digoxin in a small percentage of pa­tients (human) and lead to digoxin toxicity. These effects may persist for months after discontinuation of the tetracycline. Tetracyclines may depress plasma prothrombin activity and patients on anticoagulant (e.g., warfarin) therapy may need dosage adjustment. Tetracyclines have been reported to increase the nephrotoxic effects of methoxyflurane and tetracycline HCl or Oxytetracycline are not recommended to used with methoxyflurane. GI side effects may be increased if tetracyclines are administered concurrently with theophylline products. Tetracyclines have reportedly reduced insulin requirements in diabetic patients, but this interaction is yet to be confirmed with controlled studies.

 

Drug/Laboratory Interactions - Tetracyclines (not minocycline) may cause falsely elevated values of urine catecholamines when using fluorometric methods of determination.

Tetracyclines reportedly can cause false-positive urine glucose results if using the cupric sulfate method of determination (Benedict’s reagent, Clinitest®), but this may be the result of ascorbic acid which is found in some parenteral formulations of tetracyclines. Tetracyclines have also reportedly caused false-negative results in determining urine glucose when using the glucose oxidase method (Clinistix®, Tes-Tape®).

 

Doses -

Horses:

Warning: Doxycycline intravenously in horses has been associated with fatalities. Until further work is done demonstrating the safety of this drug, it cannot be recommended for parenteral use in this species.

 

 

Monitoring Parameters -

1)   Clinical efficacy

2)   Adverse effects

 

Client Information - Oral doxycycline products may be administered without regard to feeding. Milk or other dairy products do not significantly alter the amount of doxycycline absorbed.

 

Dosage Forms/Preparations/FDA Approval Status/Withholding Times -

 

Veterinary-Approved Products: None

 

 

Human-Approved Products:

Doxycycline (as the hyclate) Tablets and Capsules 50 mg, 100 mg; Vibramycin®  (Pfizer); Doxychel® Hyclate  (Rachelle), Doxy Caps® (Edwards); Bio-Tab® (Inter. Ethical Labs); Vibra-Tabs® (Pfizer); generic; (Rx)

 

Doxycycline (as monohydrate) Tablets and Capsules 50 mg, 100 mg; Monodox® (Oclassen) (Rx)

 

Doxycycline coated pellets (as hyclate) 100 mg; Doryx® (Parke-Davis) (Rx)

 

Doxycycline (as the monohydrate) Powder for Oral Suspension 5 mg/ml 25 mg/5 ml after reconstitution in 60 ml bottles

Vibramycin® (Pfizer); (Rx)

 

Doxycycline (as the calcium salt) Oral Syrup 10 mg/ml in 50 ml  bottles. Vibramycin® (Pfizer); (Rx)

 

Doxycycline (as the hyclate) Powder for Injection 100 mg and 200 mg vials

Vibramycin® IV (Roerig); Doxychel® Hyclate   (Rachelle); Doxy 100  & 200 (Lyphomed); generic; (Rx)

 

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