Label: DOXYCYCLINE HYCLATE capsule

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Doxycycline and other antibacterial drugs, doxycycline should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Doxycycline is an antibacterial drug synthetically derived from oxytetracycline, and is available as Doxycycline Hyclate Capsules; for oral administration.

The structural formula of doxycycline monohydrate is

with a molecular formula of C 22H 24N 2O 8∙H 2O and a molecular weight of 462.46. The chemical designation for doxycycline is 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrate. The molecular formula for doxycycline hydrochloride hemiethanolate hemihydrate is (C 22H 24N 2O 8∙HCl) 2∙C 2H 6O∙H 2O and the molecular weight is 1025.89. Doxycycline is a light-yellow crystalline powder. Doxycycline hyclate is soluble in water, while doxycycline monohydrate is very slightly soluble in water.

Doxycycline has a high degree of lipoid solubility and a low affinity for calcium binding. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form.

Inactive ingredients in the capsule formulations are: colloidal silicon dioxide, lactose anhydrous, magnesium stearate, methylcellulose, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and stearic acid. 100 mg gelatin capsule shell contains: FD&C Blue #1, titanium dioxide and gelatin. Black ink contains shellac glaze in SD-45, black iron oxide, propylene glycol, FD&C Blue #2, FD&C Red # 40, FD&C Blue # 1, D&C Yellow # 10, butyl alcohol, denatured alcohol. Each capsule, for oral administration, contains doxycycline hyclate equivalent to 100 mg of doxycycline.

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. Doxycycline is virtually completely absorbed after oral administration.

Following a 200 mg dose, normal adult volunteers averaged peak serum levels of 2.6 mcg/mL of doxycycline at 2 hours, decreasing to 1.45 mcg/mL at 24 hours. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with normal function (creatinine clearance about 75 mL/min.). This percentage excretion may fall as low as 1 to 5%/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 serum half-life.

Results of animal studies indicate that tetracyclines cross the placenta and are found in fetal tissues.

To reduce the development of drug-resistant bacteria and maintain effectiveness of doxycycline and other antibacterial drugs, doxycycline should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

This drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines.

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). This adverse reaction is more common during long-term use of the drugs, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use doxycycline in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including doxycycline, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following the use of antibacterial drugs. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing use of antibacterial drugs not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Severe skin reactions, such as exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving doxycycline. (See ADVERSE REACTIONS.) If severe skin reactions occur, doxycycline should be discontinued immediately and appropriate therapy should be instituted.

Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines including doxycycline. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Concomitant use of isotretinoin and doxycycline should be avoided because isotretinoin is also known to cause pseudotumor cerebri.

Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize.

All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in 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.

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. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

The antianabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function.

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.

Due to oral doxycycline's virtually complete absorption, side effects of the lower bowel, particularly diarrhea, have been infrequent. The following adverse reactions have been observed in patients receiving tetracyclines:

Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, inflammatory lesions (with monilial overgrowth) in the anogenital region, and pancreatitis. Hepatotoxicity has been reported rarely. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Superficial discoloration of the adult permanent dentition, reversible upon drug discontinuation and professional dental cleaning has been reported. Permanent tooth discoloration and enamel hypoplasia may occur with drugs of the tetracycline class when used during tooth development. (See WARNINGS.) Rare instances of esophagitis and esophageal ulcerations have been reported in patients receiving capsule forms of the drugs in the tetracycline class. Most of these patients took medications immediately before going to bed. (See DOSAGE AND ADMINISTRATION).

Skin: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, skin hyperpigmentation, 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.)

Immune: Hypersensitivity reactions including urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, exacerbation of systemic lupus erythematosus drug reaction with eosinophilia and systemic symptoms (DRESS), and Jarisch-Herxheimer reaction has been reported in the setting of spirochete infections treated with doxycycline.

Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported.

Other: Bulging fontanels in infants and intracranial hypertension in adults. (See WARNINGS).

When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of the thyroid gland. No abnormalities of thyroid function studies are known to occur.

To report suspected ADVERSE REACTIONS, contact Chartwell RX, LLC. at 1-845-232-1683 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.

The usual dosage and frequency of administration of doxycycline differs from that of the other tetracyclines. Exceeding the recommended dosage may result in an increased incidence of side effects.

Adults:

The usual dose of oral doxycycline is 200 mg on the first day of treatment (administered 100 mg every 12 hours) followed by a maintenance dose of 100 mg/day. In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours is recommended.

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 daily dose or divided into twice daily doses). For pediatric patients weighing over 45 kg, the usual adult dose should be used.

The therapeutic antibacterial serum activity will usually persist for 24 hours following recommended dosage.

When used in streptococcal infections, therapy should be continued for 10 days.

Administration of adequate amounts of fluid along with capsule forms of drugs in the tetracycline class is recommended to wash down the drugs and reduce the risk of esophageal irritation and ulceration. (See ADVERSE REACTIONS.)

If gastric irritation occurs, it is recommended that doxycycline be given with food or milk. The absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk.

Studies to date have indicated that administration of doxycycline at the usual recommended doses does not lead to excessive accumulation of doxycycline in patients with renal impairment.

Uncomplicated gonococcal infections in adults (except anorectal infections in men): 100 mg, by mouth, twice a day for 7 days. As an alternate single visit dose, administer 300 mg stat followed in one hour by a second 300 mg dose. The dose may be administered with food, including milk or carbonated beverage, as required.

Uncomplicated urethral, endocervical, or rectal infection in adults caused by Chlamydia trachomatis: 100 mg, by mouth twice a day for 7 days.

Nongonococcal urethritis (NGU) caused by C. trachomatis or U. urealyticum: 100 mg by mouth, twice a day for 7 days.

Syphilis – early: Patients who are allergic to penicillin should be treated with doxycycline 100 mg, by mouth, twice a day for 2 weeks.

Syphilis of more than one year's duration: Patients who are allergic to penicillin should be treated with doxycycline 100 mg, by mouth, twice a day for 4 weeks.

Acute epididymo-orchitis caused by N. gonorrhoeae: 100 mg, by mouth, twice a day for at least 10 days.

Acute epididymo-orchitis caused by C. trachomatis: 100 mg, by mouth, twice a day for at least 10 days.

For prophylaxis of malaria: For adults, the recommended dose is 100 mg daily. For children over 8 years of age, the recommended dose is 2 mg/kg given once daily up to the adult dose. Prophylaxis should begin 1–2 days before travel to the malarious area. Prophylaxis should be continued daily during travel in the malarious area and for 4 weeks after the traveler leaves the malarious area.

Doxycycline Hyclate Capsules, USP 100 mg are available as a light blue capsule filled with yellow powder imprinted with "2985" containing doxycycline hyclate, equivalent to 100 mg of doxycycline.

Bottles of 10 capsules NDC 76420-044-10 (repackaged from NDC 62135-985-xx)

Bottles of 14 capsules NDC 76420-044-14 (repackaged from NDC 62135-985-xx)

Bottles of 20 capsules NDC 76420-044-20 (repackaged from NDC 62135-985-xx)

Bottles of 28 capsules NDC 76420-044-28 (repackaged from NDC 62135-985-xx)

Dispense in a tight, light-resistant container as defined in the USP. Use child-resistant closure (as required).

Hyperpigmentation of the thyroid has been produced by members of the tetracycline class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO 4, and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO 4, and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline.

Minocycline, tetracycline PO 4, methacycline, doxycycline, tetracycline base, oxytetracycline HCl, and tetracycline HCl were goitrogenic in rats fed a low iodine diet. This goitrogenic effect was accompanied by high radioactive iodine uptake. Administration of minocycline also produced a large goiter with high radioiodine uptake in rats fed a relatively high iodine diet.

Treatment of various animal species with this class of drugs has also resulted in the induction of thyroid hyperplasia in the following: in rats and dogs (minocycline); in chickens (chlortetracycline); and in rats and mice (oxytetracycline). Adrenal gland hyperplasia has been observed in goats and rats treated with oxytetracycline.

1. Friedman JM and Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS). Baltimore, MD: The Johns Hopkins University Press, 2000: 149–195.
2. Cziezel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol 1997; 89: 524–528.
3. Horne HW Jr and Kundsin RB. The role of mycoplasma among 81 consecutive pregnancies: a prospective study. Int J Fertil 1980; 25: 315–317.
4. Hale T. Medications and Mothers Milk. 9 th edition. Amarillo, TX: Pharmasoft Publishing, 2000: 225–226.

This product's label may have been updated. For current full prescribing information, please call 1-845-232-1683.

® Penthrane is a trademark of Abbott Laboratories.

Repackaged by:

Enovachem PHARMACEUTICALS
Torrance, CA 90501