DOXYCYCLINE HYCLATE- doxycycline hyclate capsule 
REMEDYREPACK INC.

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DESCRIPTION

Doxycycline is a broad-spectrum antibiotic synthetically derived from oxytetracycline, and is available as doxycycline hyclate (doxycycline hydrochloride hemiethanolate hemihydrate) for oral administration.

The structural formula of doxycycline hyclate is

MM1

with a molecular formula of (C22H24N2O8HCl)2C2H6OH2O and a molecular weight of 1025.89. The chemical designation for doxycycline hyclate 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 monohydrochloride, compound with ethyl alcohol (2:1), monohydrate. Doxycycline hyclate is a yellow crystalline powder which is 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.

Each capsule, for oral administration, contains Doxycycline Hyclate, equivalent to 50 mg or 100 mg of Doxycycline.

Each tablet, for oral administration, contains Doxycycline Hyclate, equivalent to 100 mg of Doxycycline.

Doxycycline Hyclate Capsules USP 50 mg and 100 mg contain the following inactive ingredients: magnesium stearate and microcrystalline cellulose.

The capsule shells contain: FD&C Blue No. 1, gelatin, silicon dioxide, sodium lauryl sulfate and titanium dioxide.

Doxycycline Hyclate Tablets USP 100 mg contain the following inactive ingredients: croscarmellose sodium, FD&C Red No. 40, FD&C Yellow No. 6, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium lauryl sulfate and titanium dioxide.

CLINICAL PHARMACOLOGY

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 1-5%/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.

MICROBIOLOGY

The tetracyclines are primarily bacteriostatic and are thought to exert their antimicrobial effect by the inhibition of protein synthesis. The tetracyclines, including doxycycline, have a similar antimicrobial spectrum of activity against a wide range of gram-positive and gram-negative organisms. Cross-resistance of these organisms to tetracyclines is common.

Gram-Negative Bacteria

  • Neisseria gonorrhoeae
    • Calymmatobacterium granulomatis
      • Haemophilus ducreyi
        • Haemophilus influenzae
          • Yersinia pestis (formerly Pasteurella pestis)
            • Francisella tularensis (formerly Pasteurella tularensis)
              • Vibrio cholera (formerly Vibrio comma)
                • Bartonella bacilliformis

                  Because many strains of the following groups of gram-negative microorganisms have been shown to be resistant to tetracyclines, culture and susceptibility testing are recommended:

                  • Brucella species
                    • Escherichia coli
                      • Klebsiella species
                        • Enterobacter aerogenes
                          • Shigella species
                            • Acinetobacter species (formerly Mima species and Herellea species)

                              Gram-Positive Bacteria
                              Because many strains of the following groups of gram-positive microorganisms have been shown to be resistant to tetracycline, culture and susceptibility testing are recommended. Up to 44% of strains of Streptococcus pyogenes and 74% of Streptococcus faecalis have been found to be resistant to tetracycline drugs. Therefore, tetracycline should not be used for streptococcal disease unless the organism has been demonstrated to be susceptible.

                              • Bacteroides species
                                • Streptococcus pyogenes
                                  • Streptococcus pneumoniae
                                    • Enterococcus group (Streptococcus faecalis and Streptococcus faecium)
                                      • Alpha-hemolytic streptococci (viridans group

                                        Other Microorganisms

                                        • Rickettsiae
                                            • Chlamydia trachomatis
                                              • Mycoplasma pneumoniae
                                                • Ureaplasma urealyticum
                                                  • Borrelia recurrentis
                                                    • Treponema pallidum
                                                      • Treponema pertenue
                                                        • Clostridium species
                                                          • Fusobacterium fusiforme
                                                            • Actinomyces species
                                                              • Bacillus anthracis
                                                                • Propionibacterium acnes
                                                                  • Entamoeba species
                                                                    • Balantidium coli

                                                                      Doxycycline has been found to be active against the asexual erythrocytic forms of Plasmodium falciparum but not against the gametocytes of P. falciparum. The precise mechanism of action of the drug is not known.

                                                                      Susceptibility tests: Diffusion techniques:

                                                                      Quantitative methods that require measurement of zone diameters give the most precise estimate of the susceptibility of bacteria to antimicrobial agents. One such standard procedure1 which has been recommended for use with disks to test susceptibility of organisms to doxycycline uses the 30-mcg tetracycline-class disk or the 30-mcg doxycycline disk. Interpretation involves the correlation of the diameter obtained in the disk test with the minimum inhibitory concentration (MIC) for tetracycline or doxycycline, respectively.

                                                                      Reports from the laboratory giving results of the standard single-disk susceptibility test with a 30-mcg tetracycline-class disk or the 30-mcg doxycycline disk should be interpreted according to the following criteria:

                                                                      Zone diameter (mm)InterpretationtetracyclinedoxycyclineSusceptible15-1813-15IntermediateResistantA report ofSusceptibleindicates that the pathogen is likely to be inhibited by generally achievable blood levels. A report ofIntermediatesuggests that the organism would be susceptible if a high dosage is used or if the infection is confined to tissues and fluids in which antimicrobial levels are attained. A report ofResistantindicates that achievable concentrations are unlikely to be inhibitory, and other therapy should be selected.

                                                                      Standardized procedures require the use of laboratory control organisms. The 30-mcg tetracycline-class disk or the 30-mcg doxycycline disk should give the following zone diameters:

                                                                      OrganismZone Diameter (mm)tetracyclinedoxycyclineE. coli ATCC 2592218-2518-24S. aureus ATCC 2592319-2823-29Dilution techniques:

                                                                      Use a standardized dilution method2 (broth, agar, microdilution) or equivalent with tetracycline powder. The MIC values obtained should be interpreted according to the following criteria:

                                                                      MIC (mcg/mL)InterpretationSusceptible8IntermediateResistantAs with standard diffusion techniques, dilution methods require the use of laboratory control organisms. Standard tetracycline powder should provide the following MIC values:

                                                                      OrganismMIC (mcg/mL)E. coli ATCC 259221-4S. aureus ATCC 292130.25-1E. faecalis ATCC 292128-32P. aeruginosa ATCC 278538-32

                                                                      • Plasmodium falciparum

INDICATIONS & USAGE

CONTRAINDICATIONS

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

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 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 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 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.

PRECAUTIONS

General

As with other antibiotic preparations, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, the antibiotic should be discontinued and appropriate therapy instituted.

Bulging fontanels in infants and benign intracranial hypertension in adults have been reported in individuals receiving tetracyclines. These conditions disappeared when the drug was discontinued.

Incision and drainage or other surgical procedures should be performed in conjunction with antibiotic therapy, when indicated.

Doxycycline offers substantial but not complete suppression of the asexual blood stages of Plasmodium strains.

Doxycycline does not suppress P. falciparum's sexual blood stage gametocytes. Subjects completing this prophylactic regimen may still transmit the infection to mosquitoes outside endemic areas.

Prescribing doxycycline hyclate in the absence of proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

INFORMATION FOR PATIENTS

LABORATORY TESTS

In venereal disease, when co-existent syphilis is suspected, dark field examinations should be done before treatment is started and the blood serology repeated monthly for at least 4 months.

In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic studies, should be performed.

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 methoxyflurane has been reported to result in fatal renal toxicity.

Concurrent use of tetracycline may render oral contraceptives less effective.

DRUG & OR LABORATORY TEST INTERACTIONS

False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY

Long-term studies in animals to evaluate carcinogenic potential of doxycycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibiotics, oxytetracycline (adrenal and pituitary tumors), and minocycline (thyroid tumors).

Likewise, although mutagenicity studies of doxycycline have not been conducted, positive results in in vitro mammalian cell assays have been reported for related antibiotics (tetracycline, oxytetracycline).

Doxycycline administered orally at dosage levels as high as 250 mg/kg/day had no apparent effect on the fertility of female rats. Effect on male fertility has not been studied.

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 treatment of anthrax exposure. An expert review of published data on experiences with doxycycline use during pregnancy by TERISthe Teratogen Information Systemconcluded 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 riska. 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 (0.3%) 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 casesb.

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 agec.

Nonteratogenic effects: (See

WARNINGS

LABOR & DELIVERY

The effect of tetracyclines on labor and delivery is unknown.

NURSING MOTHERS

WARNINGS

.)

PEDIATRIC USE

See

WARNINGS

and

DOSAGE AND ADMINISTRATION

ADVERSE REACTIONS

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, and inflammatory lesions (with monilial overgrowth) in the anogenital region. Hepatotoxicity has been reported rarely. These reactions have been caused by both the oral and parenteral administration of tetracyclines. 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: 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, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus.

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

Other: bulging fontanels in infants and intracranial hypertension in adults. (See

PRECAUTIONS

General


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.

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.

DOSAGE & 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, 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 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 or U. urealyticum: 100 mg by mouth twice a day for 7 days.

Syphilisearly: 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 the 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 to 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.

weight, by mouth, twice a day for 60 days. Children weighing 100 lb or more

should receive the adult dose.

HOW SUPPLIED

Doxycycline Hyclate Capsules (equivalent to 50 mg Doxycycline) are opaque blue and opaque white capsules imprinted DAN 5535 supplied in bottles of 50.

Doxycycline Hyclate Capsules (equivalent to 100 mg Doxycycline) are opaque blue capsules imprinted DAN 5440 supplied in bottles of 50 and 500.

Doxycycline Hyclate Tablets (equivalent to 100 mg Doxycycline) are round, film-coated, light orange tablets imprinted DAN and 5553 supplied in bottles of 50 and 500.

Dispense in a tight, light-resistant container with child-resistant closure.

STORAGE AND HANDLING

Store below 30(86

ANIMAL PHARMACOLOGY & OR TOXICOLOGY


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.

REFERENCES

1. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests, Fourth Edition. Approved Standard NCCLS Document M2-A4, Vol. 10, No. 7 NCCLS, Villanova, PA, April 1990.

2. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, Second Edition. Approved Standard NCCLS Document M7-A2, Vol. 10, No. 8 NCCLS, Villanova, PA, April 1990.

3. aFriedman JM and Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS). Baltimore, MD: The Johns Hopkins University Press, 2000: 149-195.

dHale T. Medications and Mothers Milk. 9th edition. Amarillo, TX: Pharmasoft Publishing, 2000: 225-226.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION

DRUG: Doxycycline Hyclate

GENERIC: Doxycycline Hyclate

DOSAGE: CAPSULE

ADMINSTRATION: ORAL

NDC: 49349-949-04

STRENGTH:100 mg

COLOR: blue

SHAPE: CAPSULE

SCORE: No score

SIZE: 22 mm

IMPRINT: 14

QTY: 14

MM2

MM3

DOXYCYCLINE HYCLATE 
doxycycline hyclate capsule
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:49349-949
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
DOXYCYCLINE HYCLATE (UNII: 19XTS3T51U) (DOXYCYCLINE ANHYDROUS - UNII:334895S862) DOXYCYCLINE ANHYDROUS100 mg
Inactive Ingredients
Ingredient NameStrength
FD&C BLUE NO. 1 (UNII: H3R47K3TBD)  
GELATIN (UNII: 2G86QN327L)  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
SODIUM LAURYL SULFATE (UNII: 368GB5141J)  
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
MAGNESIUM STEARATE (UNII: 70097M6I30)  
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
Product Characteristics
ColorblueScoreno score
ShapeCAPSULE (CAPSULE) Size22mm
FlavorImprint Code DAN;5440
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:49349-949-0414 in 1 BLISTER PACK; Type 0: Not a Combination Product03/29/201210/07/2016
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA06203103/29/201210/07/2016
Labeler - REMEDYREPACK INC. (829572556)

Revised: 10/2016
 
REMEDYREPACK INC.