DORYX 100 MG Delayed Release Oral Capsule

WARNINGS

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.

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.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including DORYX ® Capsules, 75 mg and 100 mg, 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 antibiotic use.

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 antibiotic use not directed against C.

difficile may need to be discontinued.

Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C.

difficile , and surgical evaluation should be instituted as clinically indicated.

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 six 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 been noted in animals treated early in pregnancy.

If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking these drugs, the patient should be apprised of 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.

DRUG INTERACTIONS

Drug interactions Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.

Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines in conjunction with penicillin.

Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, and iron-containing preparations.

Absorption of tetracyclines is impaired by bismuth subsalicylate.

Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline.

The concurrent use of tetracycline and Penthrane ® (methoxyflurane) has been reported to result in fatal renal toxicity.

Concurrent use of tetracycline may render oral contraceptives less effective.

OVERDOSAGE

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.

DESCRIPTION

DORYX Capsules contain specially coated pellets of doxycycline hyclate, a broad-spectrum antibiotic synthetically derived from oxytetracycline, in a delayed-release formulation for oral administration.

The structural formula for doxycycline hyclate is with a molecular formula of C 22 H 24 N 2 O 8 , HCl, ½ C 2 H 6 O, ½ H 2 O and a molecular weight of 512.9.

The chemical designation for doxycycline hyclate is [4S (4aR, 5S, 5aR, 6R, 12aS)]-4-(dimethylamino)- 1,4,4a, 5,5a, 6, 11,12a-octahydro-3, 5,10,12,12a-pentahydroxy-6-methyl-1, 11-deoxonapthtacene-2- carboxamide monohydrochloride, compound with ethyl alcohol (2:1), monohydrate.

Doxycycline hyclate is a yellow crystalline powder soluble in water and in solutions of alkali hydroxides and carbonates.

Doxycycline has a high degree of lipid 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 formulation are: lactose; microcrystalline cellulose; povidone; starch wheat; magnesium stearate; cellulosic polymer coating.

The capsule shell and/or band contains FD and C blue No.1; FD and C yellow No.

6; D and C yellow No.10; gelatin, silicon dioxide; sodium lauryl sulfate; titanium dioxide.

The structural formula for doxycycline hyclate is with a molecular formula of C22H24N2O8, HCl, ½ C2H6O, ½ H2O and a molecular weight of 512.9.

The chemical designation for doxycycline hyclate is [4S (4aR, 5S, 5aR, 6R, 12aS)]-4-(dimethylamino)- 1,4,4a, 5,5a, 6, 11,12a-octahydro-3, 5,10,12,12a-pentahydroxy-6-methyl-1, 11-deoxonapthtacene-2- carboxamide monohydrochloride, compound with ethyl alcohol (2:1), monohydrate.

HOW SUPPLIED

DORYX ® (doxycycline hyclate) Delayed-Release Capsules, 100 mg have a dark yellow transparent body, with light blue opaque cap; the capsule bearing the inscription “DORYX” and “WC” in a circle, printed in white.

Pellets are colored yellow.

Each capsule contains specially coated pellets of doxycycline hyclate equivalent to 100 mg of doxycycline, supplied in: Bottles of 50 capsules…N 0430-0838-19 DORYX ® (doxycycline hyclate) Delayed-Release Capsules, 75 mg have an orange transparent body, with green opaque cap; the capsule bearing the inscription “DORYX” and “75 mg” in black.

Pellets are colored yellow.

Each capsule contains specially coated pellets of doxycycline hyclate equivalent to 75 mg of doxycycline, supplied in: Bottles of 60 capsules…N 0430-0836-20

GERIATRIC USE

Geriatric use Clinical studies with DORYX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of the decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain the effectiveness of DORYX and other antibacterial drugs, DORYX 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.

PEDIATRIC USE

Pediatric use See WARNINGS and DOSAGE AND ADMINISTRATION.

PREGNANCY

Pregnancy Teratogenic Effects.

Pregnancy Category D: There are no adequate and well-controlled studies on the use of doxycycline in pregnant women.

The vast majority of reported experience with doxycycline during human pregnancy is short-term, first trimester exposure.

There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for the treatment of anthrax exposure.

An expert review of published data on experiences with doxycycline use during pregnancy by TERIS – the Teratogen Information System – concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no risk 3 .

A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy.

Sixty-three (0.19%) of the controls and 56 (0.30%) of the cases were treated with doxycycline.

This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (i.e., in the second and third months of gestation) with the exception of a marginal relationship with neural tube defect based on only two exposed cases 4 .

A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10 days with doxycycline during early first trimester.

All mothers reported their exposed infants were normal at 1 year of age 5 .

Nonteratogenic effects: (See WARNINGS).

NUSRING MOTHERS

Nursing Mothers Tetracyclines are excreted in human milk, however, the extent of absorption of tetracyclines including doxycycline, by the breastfed infant is not known.

Short-term use by lactating women is not necessarily contraindicated; however, the effects of prolonged exposure to doxycycline in breast milk are unknown 6 .

Because of the potential for serious adverse reactions in nursing infants from doxycycline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

(See WARNINGS.)

INFORMATION FOR PATIENTS

Information for Patients: Patients taking doxycycline for malaria prophylaxis should be advised: 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 (e.g., staying in well-screened areas, using mosquito nets, covering the body with clothing, and using an effective insect repellant).

that doxycycline prophylaxis: should begin 1-2 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.

All patients taking doxycycline should be advised: to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (e.g., skin eruptions, etc.) occurs.

Sunscreen or sunblock should be considered (See WARNINGS ).

to drink fluids liberally along with doxycycline 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.

However, the absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk.

(See Drug interactions).

that the absorption of tetracyclines is reduced when taking bismuth subsalicylate (See Drug interactions).

that the use of doxycycline might increase the incidence of vaginal candidiasis.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued.

Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic.

If this occurs, patients should contact their physician as soon as possible.

Patients should be counseled that antibacterial drugs including DORYX should only be used to treat bacterial infections.

They do not treat viral infections (e.g., the common cold).

When DORYX is prescribed to treat a bacterial infection, patients should be told 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 or other antibacterial drugs in the future.

DOSAGE AND ADMINISTRATION

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.

The maintenance dose may be administered as a single dose or as 50 mg every 12 hours.

In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours is recommended.

For children above eight years of age: The recommended dosage schedule for children weighing 100 pounds or less is 2 mg/lb of body weight divided into two doses on the first day of treatment, followed by 1 mg/lb of body weight given as a single daily dose or divided into two doses on subsequent days.

For more severe infections up to 2 mg/lb of body weight may be used.

For children over 100 lb, 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 and tablet 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, doxycycline may be given with food or milk.

Studies to date have indicated that administration of doxycycline at the usual recommended doses does not lead to excessive accumulation of the antibiotic 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 and 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.

Inhalational anthrax (post-exposure): ADULTS: 100 mg, of doxycycline, by mouth, twice a day for 60 days.

CHILDREN: weighing less than 100 lb (45 kg); 1 mg/lb (2.2 mg/kg) of body weight, by mouth, twice a day for 60 days.

Children weighing 100 lb or more should receive the adult dose.