Doxycycline Calcium, Doxycycline Hyclate, Doxycycline Monohydrate
Doxycycline is a semisynthetic tetracycline antibiotic derived from oxytetracycline.
Pharmacokinetics
Absorption
Approximately 90-100% of an oral dose of doxycycline hyclate is absorbed from the GI tract in fasting adults. Following oral administration of capsules containing doxycycline hyclate in fasting adults with normal renal function, peak serum concentrations of doxycycline are attained within 1.5-4 hours and average 1.5-2.1 mcg/mL following a single 100-mg dose and 2.6-3 mcg/mL following a single 200-mg dose.
Following oral administration of a single 200-mg dose of doxycycline monohydrate in healthy adults, peak serum concentrations of doxycycline are attained within approximately 2.5 hours and average about 3.6 mcg/mL. GI absorption of doxycycline salts may be reduced up to 20% by food and/or milk; however, the effect is not usually clinically important. In one study, food delayed time to peak plasma concentration of doxycycline and increased the area under the plasma concentration-time curve (AUC) and average peak plasma concentration of the drug.
Because tetracyclines readily chelate divalent or trivalent cations including aluminum, calcium, iron, and magnesium, concurrent oral administration of antacids and other drugs containing these cations may decrease oral absorption of doxycycline preparations. Of the currently available tetracyclines, doxycycline has the least affinity for calcium ions. In one study following IV infusion over 1 hour of 100 mg of doxycycline as the hyclate, peak serum concentrations of the drug averaged 2.5 mcg/mL. In the same study, IV infusion over 2 hours of 200 mg of doxycycline as the hyclate resulted in average peak serum concentrations of the drug of 3.6 mcg/mL.
Elimination
The serum half-life of doxycycline is 14-17 hours after a single dose and 22-24 hours after multiple doses in patients with normal renal function. In patients with severe renal impairment, the serum half-life of doxycycline is reported to be 18-26 hours after a single dose, and 20-30 hours after multiple doses. It appears that serum half-life of doxycycline is not altered in patients undergoing hemodialysis. In patients with normal renal function, approximately 20-26% of a single oral or IV dose of doxycycline is excreted in urine and 20-40% is excreted in feces within 48 hours as active drug. In patients with creatinine clearances less than 10 mL/minute, the fraction of doxycycline excreted in urine within 72 hours may decrease to about 1-5%. Although it was previously suggested that doxycycline is partially metabolized in the liver, recent studies indicate that the drug is not metabolized but is partially deactivated in the intestine by chelate formation.
Chemistry and Stability
Chemistry
Doxycycline is a semisynthetic tetracycline antibiotic derived from oxytetracycline. Doxycycline is commercially available as the calcium, the hyclate, and the monohydrate salts. Doxycycline hyclate and doxycycline monohydrate occur as yellow, crystalline powders. The hyclate is soluble in water and slightly soluble in alcohol; the monohydrate is very slightly soluble in water and sparingly soluble in alcohol. Doxycycline calcium is formed in situ during the manufacturing process. Following reconstitution of doxycycline hyclate powder for IV administration with sterile water for injection, solutions have a pH of 1.8-3.3.
Stability
Doxycycline hyclate capsules and film-coated tablets should be stored in tight, light-resistant containers at a temperature of 30°C or less, preferably between 15-30°C. Delayed release capsules containing partially enteric-coated pellets of doxycycline hyclate should be stored at a controlled room temperature less than 25°C. Doxycycline monohydrate 50- and 100-mg capsules and doxycycline hyclate 20-mg tablets should be stored in tight, light-resistant containers at 15-30°C. Following reconstitution with water, doxycycline monohydrate oral suspensions are stable for 2 weeks at room temperature.
Limited data indicate that doxycycline tablets that have been crushed and mixed with food or drinks (chocolate pudding, regular or low-fat chocolate milk, apple juice with table sugar, low-fat milk) are stable for 24 hours at room temperature (22-26°C) or when refrigerated at 2-8°C; crushed doxycycline tablets mixed with low-fat chocolate milk were stable when refrigerated for 1 week.
In addition, crushed doxycycline tablets were stable for at least 6 days when wrapped in aluminum foil and stored at room temperature. When reconstituted and diluted with 0.9% sodium chloride or 5% dextrose, doxycycline hyclate IV solutions containing 0.1-1 mg of doxycycline per mL are stable for 48 hours at 25°C; when reconstituted and diluted with Ringer’s, 10% invert sugar, Normosol-M® in D5W, Normosol-R® in D5W, Plasma-Lyte® 56 in 5% dextrose, or Plasma-Lyte® 148 in 5% dextrose, doxycycline hyclate IV solutions containing 0.1-1 mg/mL are stable for 12 hours at room temperature.
The manufacturer states that doxycycline hyclate solutions prepared with any of these infusion solutions are stable for 72 hours at 2-8°C when protected from direct sunlight and artificial light; however, after storage in this manner, infusion of these solutions must be completed within 12 hours. Doxycycline hyclate IV solutions diluted to a concentration of 0.1-1 mg/mL with lactated Ringer’s injection or 5% dextrose in lactated Ringer’s injection must be infused within 6 hours to ensure stability. During infusion, all doxycycline hyclate IV solutions must be protected from direct sunlight.
Solutions of doxycycline hyclate containing 10 mg of doxycycline per mL may be frozen immediately after reconstitution with sterile water for injection and are stable for 8 weeks when stored at -20°C. If the solutions are warmed to facilitate thawing, care should be taken to avoid heating after thawing is completed. Once thawed, solutions should not be refrozen.
Preparations
Doxycycline Calcium Oral Suspension 50 mg (of doxycycline) per 5 Vibramycin® Calcium Syrup, mL (with parabens, povidone, propylene glycol, and sodium metabisulfite) Pfizer Doxycycline Hyclate Oral Capsules 50 mg (of doxycycline) Vibramycin® Hyclate, Pfizer 100 mg (of doxycycline) Vibramycin® Hyclate, Pfizer Capsules, delayed- 100 mg (of doxycycline) Doryx®, (with povidone) Warner release Chilcott (containing partially enteric-coated pellets)Tablets 20 mg (of doxycycline) Periostat®,CollaGenex Tablets, film- 100 mg (of doxycycline) Vibra-Tabs®, (with propylene coated glycol) Pfizer Parenteral For injection, for 100 mg (of doxycycline) Doxy 100®, (with ascorbic acid IV use only 480 mg and mannitol 300 mg) American Pharmaceutical Partners Vibramycin® Hyclate Intravenous, (with ascorbic acid 480 mg) Pfizer 200 mg (of doxycycline) Vibramycin Hyclate Intravenous, (with ascorbic acid 960 mg) Pfizer Doxycycline Monohydrate Oral Capsules 50 mg (of doxycycline) Monodox®, Watson 100 mg (of doxycycline) Monodox®, Watson For suspension 25 mg (of doxycycline) per 5 Vibramycin® Monohydrate, (with mL parabens) Pfizer