Doxycycline Hyclate

In clinical trials involving a total of 1436 patients, adverse experiences from all causalities were monitored across treatment groups.

In the Circulatory System category, 10 subjects (1.6%) in the ATRIDOX (doxycycline hyclate) ® group were reported as having “unspecified essential hypertension.” Only 1 subject (0.2%) in the Vehicle group, and none in the Scaling and Root Planing or Oral Hygiene groups were reported to have “unspecified essential hypertension.” In all cases, the event occurred anywhere from 13 to 134 days post treatment. There is no known association of oral administration of doxycycline with essential hypertension.

Two patients in the polymer vehicle group and none in the ATRIDOX (doxycycline hyclate) ® group (0.2% for both groups combined) reported adverse events consistent with a localized allergic response.

Sex, age, race and smoking status did not appear to be correlated with adverse events.

The following table lists the incidence of treatment-emergent adverse events from all causalities, across all treatment groups, occurring in ≥ 1% of the entire study population.

Advise patients taking DORYX MPC for malaria prophylaxis:

• that no present-day antimalarial agent, including doxycycline, guarantees protection against malaria.
• to avoid being bitten by mosquitoes by using personal protective measures that help avoid contact with mosquitoes, especially from dusk to dawn (for example, staying in well-screened areas, using mosquito nets, covering the body with clothing, and using an effective insect repellent).
• that doxycycline prophylaxis:
  • should begin 1 to 2 days before travel to the malarious area,
  • should be continued daily while in the malarious area and after leaving the malarious area,
  • should be continued for 4 further weeks to avoid development of malaria after returning from an endemic area,
  • should not exceed 4 months.

Advise all patients taking DORYX MPC:

• to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototo xicity (for example, skin eruptions, etc.) occurs. Sunscreen or sunblock should be considered [see WARNINGS AND PRECAUTIONS]
• to drink fluids liberally along with DORYX MPC to reduce the risk of esophageal irritation and ulceration [see ADVERSE REACTIONS]
• that the absorption of tetracyclines is reduced when taken with foods, especially those that contain calcium. [see DRUG INTERACTIONS]
• that if gastric irritation occurs, DORYX MPC may be given with food or milk [see CLINICAL PHARMACOLOGY]
• that the absorption of tetracyclines is reduced when taken with antacids containing aluminum, calcium or magnesium, bismuth subsalicylate, and iron-containing preparations [see DRUG INTERACTIONS].
• that the use of doxycycline might increase the incidence of vaginal candidiasis.

Advise patients that diarrhea is a common problem caused by antibacterial drugs which usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without s tomach cramps and fever) even as late as two or more months after having taken the last dose of antibacterial. If this occurs, patients should contact their physician as soon as possible.

Counsel patients that antibacterial drugs including DORYX MPC should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When DORYX MPC is prescribed to treat a bacterial infection, patients should be to ld that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by DORYX MPC or other antibacterial drugs in the future.

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 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 Vibramycin, 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 Vibramycin. 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 Vibramycin 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.

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 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.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Antibacterial; semisynthetic tetracycline antibiotic derived from oxytetracycline.103 111 113 114

Absorption

Bioavailability

90–100% absorbed from GI tract in fasting adults;b peak serum concentrations attained within 1.5–4 hours.111 b

Food

GI absorption reduced up to 20% by food and/or milk;b effect not considered clinically important.111 b

Divalent and trivalent cations, including aluminum, calcium, iron, and magnesium, may decrease oral absorption as a result of chelation with the drug.b

Distribution

Extent

Widely distributed into body tissues and fluids.a

Only small amounts diffuse into CSF.a

Readily crosses the placentaa and is distributed into milk.111 a

Plasma Protein Binding

25–93%.a

Elimination

Metabolism

Does not appear to be metabolized in the liver, but is partially inactivated in the intestine by chelate formation.b

Elimination Route

Excreted into the GI tract via bile and by nonbiliary routes.111 b 20–26% of an oral or IV dose excreted in urine and 20–40% excreted in feces.111 113 b

Half-life

14–17 hours after a single dose and 22–24 hours after multiple doses.b

Special Populations

Patients with severe hepatic impairment or biliary obstruction: Serum concentrations and half-life may be increased.a

Patients with severe renal impairment: Half-life 18–26 hours after a single dose and 20–30 hours after multiple doses.b

• Advise patients that antibacterials (including doxycycline) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).c

• Importance of completing full course of therapy, even if feeling better after a few days.111 c

• Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with doxycycline or other antibacterials in the future.c

• Importance of drinking sufficient quantities of fluids when taking capsules or tablets to reduce the risk of esophageal irritation and ulceration.111

• Advise patients that doxycycline absorption is reduced when taken with foods, especially those containing calcium, but is not markedly influenced by simultaneous ingestion with food or milk.111

• Advise patients that doxycycline may increase the incidence of vaginal candidiasis.111

• Advise patients that doxycycline may decrease effectiveness of oral contraceptives and that alternative nonhormonal contraceptive measures should be used.a

• Advise patients to avoid excessive sunlight or artificial UV light and to discontinue the drug at the first sign of skin erythema and if phototoxicity (e.g., skin eruption) occurs;111 consider use of sunscreen or sunblock.111

• Advise patients using the drug for malaria prevention that no antimalarial agent (including doxycycline) guarantees protection against malaria.111 Importance of using personal protective measures to avoid mosquito bites (e.g., staying in well-screened areas, using mosquito nets, covering body with clothing, using an effective insect repellent), especially from dusk to dawn.111

• Advise patients using the drug for malaria prevention that such prophylaxis should begin 1–2 days before travel to the malarious area, be taken daily while in the malarious area, and continued for 4 weeks (but not >4 weeks) after leaving the area.111

• Advise travelers who plan presumptive self-treatment in the event of a possible malarial infection to keep an amount of doxycycline and quinine sufficient for self-treatment in their possession during travel and to take the regimen promptly in the event of a febrile illness during or after their travel if professional medical care is not readily available.122 158

• Advise travelers that presumptive self-treatment of malaria is an interim measure and that they should seek medical evaluation as soon as possible.122 158

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.111 (See Fetal/Neonatal Morbidity under Cautions.)

• Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, and any concomitant illnesses.111

• Importance of informing patients of other important precautionary information. (See Cautions.)

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

The structural formula of doxycycline monohydrate is

with a molecular formula of C22H24N2O8∙H2O 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 (C22H24N2O8∙HCl)2∙C2H6O∙H2O 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.

Inert ingredients in the capsule formulations are: hard gelatin capsules (which may contain Blue 1 and other inert ingredients); magnesium stearate; microcrystalline cellulose; sodium lauryl sulfate.

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 and tablet 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, 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, and drug reaction with eosinophilia and systemic symptoms (DRESS).

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.

Hyperpigmentation of the thyroid has been produced by members of the tetracycline class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO4, and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO4, and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline.

Minocycline, tetracycline PO4, 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.