THE USUAL DOSAGE AND FREQUENCY OF ADMINISTRATION OF INTRAVENOUS Doxclik (100 TO 200 MG/DAY) DIFFERS FROM THAT OF THE OTHER TETRACYCLINES (1 TO 2 G/DAY). EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE EFFECTS.
Studies to date have indicated that Doxclik at the usual recommended doses does not lead to excessive accumulation of the antibiotic in patients with renal impairment.

Adults
The usual dosage of intravenous Doxclik is 200 mg on the first day of treatment administered in one or two infusions. Subsequent daily dosage is 100 to 200 mg depending upon the severity of infection, with 200 mg administered in one or two infusions. In the treatment of primary and secondary syphilis, the recommended dosage is 300 mg daily for at least 10 days. In the treatment of inhalational anthrax (post-exposure) the recommended dose is 100 mg of Doxclik, twice a day. Parenteral therapy is only indicated when oral therapy is not indicated and should not be continued over a prolonged period of time. Oral therapy should be instituted as soon as possible. Therapy must continue for a total of 60 days.

Pediatric Patients
For all pediatric patients weighing less than 45 kg with severe or life-threatening infections (e.g., anthrax, Rocky Mountain spotted fever), the recommended dosage is 2.2 mg/kg of body weight administered every 12 hours. Children weighing 45 kg or more should receive the adult dose (see WARNINGS and PRECAUTIONS). For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dosage schedule is 4.4 mg/kg of body weight divided into two doses on the first day of treatment, followed by a maintenance dose of 2.2 mg/kg of body weight (given as a single dose or divided into twice daily doses). For pediatric patients weighing over 45 kg, the usual adult dose should be used. In the treatment of inhalational anthrax (post-exposure) the recommended dose is 2.2 mg/kg of body weight, twice a day in the children weighing less than lb 45 kg. Parenteral therapy is only indicated when oral therapy is not indicated and should not be continued over a prolonged period of time. Oral therapy should be instituted as soon as possible. Therapy must continue for a total of 60 days.

General
The duration of infusion may vary with the dose (100 to 200 mg per day), but is usually one to four hours. A recommended minimum infusion time for 100 mg of a 0.5 mg/mL solution is one hour. Therapy should be continued for at least 24 to 48 hours after symptoms and fever have subsided. The therapeutic antibacterial serum activity will usually persist for 24 hours following recommended dosage.
Intravenous solutions should not be injected intramuscularly or subcutaneously. Caution should be taken to avoid the inadvertent introduction of the intravenous solution into the adjacent soft tissue.
Preparation of Solution:
1. To prepare a solution containing 10 mg/mL, the contents of the vial should be reconstituted with 10 mL of Sterile Water for Injection IP.
2. Each 100 mg of Doxycycline (i.e. withdraw entire solution from the 100 mg vial) is further diluted with 100 to 1000 ml of the intravenous solutions listed below: Reconstituted solution should be immediately diluted to 100 to 1000 ml of intravenous solution listed below:
A. 0.9% Sodium Chloride Injection IP
B. 5% Dextrose Injection IP
This will result in desired concentrations of 0.1 to 1 mg/mL. Concentrations lower than 0.1 mg/mL or higher than 1 mg/mL are not recommended.

Stability
Doxycycline is stable for 4 hours in solution when diluted with Sodium Chloride Injection, or 5% Dextrose Injection, to concentrations between 1 mg/mL and 0.1 mg/mL and stored at 25°C. Doxycycline in these solutions is stable under fluorescent light for 4 hours but must be protected from direct sunlight during storage and infusion. Reconstituted solutions (1 to 0.1 mg/mL) may be stored up to 4 hours prior to start of infusion if refrigerated and protected from sunlight and artificial light. Infusion must then be completed within 4 hours. Solutions must be used within these time periods or discarded.
When diluted with or Dextrose 5% in infusion of the solution (ca. 1 mg/mL) or lower concentrations (not less than 0.1 mg/mL) must be completed within 4 hours after reconstitution to ensure adequate stability. During infusion, the solution must be protected from direct sunlight. Solutions must be used within this time period or discarded.
Parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit.

TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT BE USED IN THIS AGE GROUP, EXCEPT FOR ANTHRAX, INCLUDING INHALATIONAL ANTHRAX, (POST-EXPOSURE), UNLESS OTHER DRUGS ARE NOT LIKELY TO BE EFFECTIVE OR ARE CONTRAINDICATED.
This adverse reaction is more common during long-term use of the drugs but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Tetracycline drugs, therefore, should not be used in this age group unless other drugs are not likely to be effective or are contraindicated.
Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema.
The anti-anabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of Doxclik in patients with impaired renal function.

As with other antibiotic preparations, use of this drug may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, the antibiotic should be discontinued and appropriate therapy instituted. In venereal diseases when coexistent syphilis is suspected, a dark field examination should be done before treatment is started and the blood serology repeated monthly for at least 4 months. Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.
In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal and hepatic studies should be performed. All infections due to group A beta-hemolytic streptococci should be treated for at least 10 days. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline in conjunction with penicillin.

Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracycline may render oral contraceptives less effective.

The use of drugs of the tetracycline class during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy. Tetracyclines are present in the milk of lactating women who are taking a drug in this class. It should be avoided during lactation.

Usage in pediatric patients
The use of Doxycycline Intravenous in children under 8 years is not recommended because safe conditions for its use have not been established.
As with other tetracyclines, doxycycline forms a stable calcium complex in any bone-forming tissue. A decrease in the fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued.

Usage in Geriatric patients:
In general, doxycycline dose selection for the geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In this age group any antibiotic may cause diarrhea, nausea, vomiting, anorexia, and hypersensitivity reactions.

Skin: Maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above. (See WARNINGS).
Renal Toxicity: Rise in BUN has been reported and is apparently dose related. (See WARNINGS). Hypersensitivity Reactions: Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, pericarditis and exacerbation of systemic lupus erythematosus.
Bulging fontanels in infants and benign intracranial hypertension in adults have been reported in individuals receiving full therapeutic dosages. These conditions disappeared rapidly when the drug was discontinued.
Blood: Hemolytic anemia, thrombocytopenia, neutropenia and eosinophilia have been reported. When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function studies are known to occur.

Cross resistance with other tetracyclines is common.
PHARMACODYNAMICS
Doxycycline is primarily bacteriostatic and is believed to exert its antimicrobial effect by the inhibition of protein synthesis. Doxycycline is active against a wide range of Gram-positive and Gram-negative bacteria and certain other micro-organisms. Doxycycline exhibits time‐dependent killing at two to four times the MIC, but dose‐dependent killing at eight to 16 times the MIC of the organisms tested. Optimal dose‐dependent killing may be achieved using 200 mg every 12 h. In mild to moderate infections, time‐dependent killing is sufficiently effective, and doxycycline may be dosed as 100 mg every 12 h or 200 mg every 24 h.
PHARMACOKINECTICS
Following a single 100 mg dose administered in a concentration of 0.4 mg/mL in a one-hour infusion, normal adult volunteers average a peak of 2.5 mcg/mL, while 200 mg of a concentration of 0.4 mg/mL administered over two hours averaged a peak of 3.6 mcg/mL. Excretion of doxycycline by the kidney is about 40 percent/72 hours in individuals with normal function (creatinine clearance about 75 mL/min.). This percentage excretion may fall as low as 1-5 percent/72 hours in individuals with severe renal insufficiency (creatinine clearance below 10 mL/min.). Studies have shown no significant difference in serum half-life of doxycycline (range 18-22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter this serum half-life of doxycycline

The drugs in the tetracycline class have closely similar antimicrobial spectra, and cross resistance among them is common. Microorganisms may be considered susceptible to Doxycycline (likely to respond to Doxclik therapy) if the minimum inhibitory concentration (M.I.C.) is not more than 4 mcg/mL. Microorganisms may be considered intermediate (harboring partial resistance) if the M.I.C. is 4 to 12.5 mcg/mL and resistant (not likely to respond to therapy) if the M.I.C. is greater than 12.5 mcg/mL.
Susceptibility Plate Testing: If the Kirby-Bauer method of disc susceptibility is used, a 30 mcg Doxclik disc should give a zone of at least 16 mm when tested against a Doxclik-susceptible strain. A tetracycline disc may be used to determine microbial susceptibility. If the Kirby-Bauer method of disc susceptibility is used, a 30 mcg tetracycline disc should give a zone of at least 19 mm when tested against a tetracycline-susceptible bacterial strain.
Tetracyclines are readily absorbed and are bound to plasma proteins in varying degree. They are concentrated by the liver in the bile, and excreted in the urine and feces at high concentrations and in a biologically active form.
Following a 100 mg single dose administered in a concentration of 0.4 mg/mL in a one-hour infusion, normal adult volunteers average a peak of 2.5 mcg/mL, while 200 mg of a concentration of 0.4 mg/mL administered over two hours average a peak of 3.6 mcg/mL.
Excretion of Doxycycline by the kidney is about 40 percent/72 hours in individuals with normal function (creatinine clearance about 75 mL/min). This percentage excretion may fall as low as 1 to 5 percent/72 hours in individuals with severe renal insufficiency (creatinine clearance below 10 mL/min). Studies have shown no significant difference in serum half-life of Doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter this serum half-life of Doxycycline.