Name of the medicinal product

Doryx

Qualitative and quantitative composition

Dosage Forms And Strengths

DORYX MPC (doxycycline hyclate delayed-release tablets), 60 mg and 120 mg are white, oval tablets containing yellow pellets and debossed on one face with “D6” and “DC”, respectively, and plain on the other. Each tablet contains doxycycline 60 mg or 120 mg (equivalent to doxycycline hyclate 69.4 mg or 138.8 mg).

Storage And Handling

DORYX MPC (doxycycline hyclate delayed-release tablets), 60 mg and 120 mg are white, oval tablets containing yellow pellets and debossed on one face with “D6” and “DC”, respectively, and plain on the other. Each tablet contains doxycycline 60 mg or 120 mg (equivalent to doxycycline hyclate 69.4 mg or 138.8 mg).

The 60 mg tablet is supplied in bottles of 120 tablets NDC 51862-560-12
The 120 mg tablet is supplied in bottles of 60 tablets. NDC 51862-559-60

Store at 25° C (77° F); excursions permitted to 15°C to 30° C (59°F to 86° F). Dispense in a tight, light-resistant container (USP).

Manufactured by: Mayne Pharma International Pty Ltd 1538 Main North Road Salisbury South, SA 5106 Australia. Revised: May 2017

Therapeutic indications

Rickettsial Infections

DORYX MPC is indicated for treatment of Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae.

Sexually Transmitted Infections

DORYX MPC is indicated for treatment of the following sexually transmitted infections:

Uncomplicated urethral, endocervical or rectal infections in adults caused by Chlamydia trachomatis.
Nongonococcal urethritis caused by Ureaplasma urealyticum.
Lymphogranuloma venereum caused by Chlamydia trachomatis.
Granuloma inguinale caused by Klebsiella granulomatis.
Uncomplicated gonorrhea caused by Neisseria gonorrhoeae.
Chancroid caused by Haemophilus ducreyi.

Respiratory Tract Infections

DORYX MPC is indicated for treatment of the following respiratory tract infections:

Respiratory tract infections caused by Mycoplasma pneumoniae.
Psittacosis (ornithosis) caused by Chlamydophila psittaci.
Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended.
Doxycycline is indicated for treatment of infections caused by the following microorganisms, when bacteriological testing indicates appropriate susceptibility to the drug:
- Respiratory tract infections caused by Haemophilus influenzae.
- Respiratory tract infections caused by Klebsiella species.
- Upper respiratory infections caused by Streptococcus pneumoniae.

Specific Bacterial Infections

DORYX MPC is indicated for treatment of the following specific bacterial infections:

Relapsing fever due to Borrelia recurrentis.
Plague due to Yersinia pestis.
Tularemia due to Francisella tularensis.
Cholera caused by Vibrio cholerae.
Campylobacter fetus infections caused by Campylobacter fetus.
Brucellosis due to Brucella species (in conjunction with streptomycin).
Bartonellosis due to Bartonella bacilliformis.

Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended.

DORYX MPC is indicated for treatment of infections caused by the following gram-negative microorganisms, when bacteriological testing indicates appropriate susceptibility to the drug:

Escherichia coli
Enterobacter aerogenes
Shigella species
Acinetobacter species
Urinary tract infections caused by Klebsiella species.

Ophthalmic Infections

DORYX MPC is indicated for treatment of the following ophthalmic infections:

Trachoma caused by Chlamydia trachomatis, although the infectious agent is not always eliminated as judged by immunofluorescence.
Inclusion conjunctivitis caused by Chlamydia trachomatis.

Anthrax Including Inhalational Anthrax (Post-Exposure)

DORYX MPC is indicated for treatment of Anthrax due to Bacillus anthracis, including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis.

Alternative Treatment For Selected Infections When Penicillin Is Contraindicated

DORYX MPC is indicated as an alternative treatment for the following selected infections when penicillin is contraindicated:

Syphilis caused by Treponema pallidum.
Yaws caused by Treponema pallidum subspecies pertenue.
Listeriosis due to Listeria monocytogenes.
Vincent’s infection caused by Fusobacterium fusiforme.
Actinomycosis caused by Actinomyces israelii.
Infections caused by Clostridium species.

Adjunctive Therapy For Acute Intestinal Amebiasis And Severe Acne

In acute intestinal amebiasis, DORYX MPC may be a useful adjunct to amebicides. In severe acne, DORYX MPC may be useful adjunctive therapy.

Prophylaxis Of Malaria

DORYX MPC is indicated for the prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (less than 4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains.

Usage

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

Dosage (Posology) and method of administration

Important Dosage And Administration Instructions

DORYX MPC is not substitutable on a mg per mg basis with other oral doxycyclines. To avoid prescribing errors, do not substitute DORYX MPC for other oral doxycyclines on a mg per mg basis because of differing bioavailability.
Do not chew or crush tablets.
The recommended dosage, frequency of administration and weight-based dosage recommendations of DORYX MPC differ from that of the other tetracyclines. Exceeding the recommended dosage may result in an increased incidence of adverse reactions.
Administer DORYX MPC with an adequate amount of fluid to wash down the drug and reduce the risk of esophageal irritation and ulceration.
If gastric irritation occurs, DORYX MPC may be given with food or milk.

Switching From DORYX To DORYX MPC

When switching from DORYX to DORYX MPC:

A 60 mg dose of DORYX MPC will replace a 50 mg dose of DORYX
A 120 mg dose of DORYX MPC will replace a 100 mg dose of DORYX

Dosage In Adult Patients

The usual dosage of DORYX MPC is 240 mg on the first day of treatment (administered 120 mg every 12 hours) followed by a maintenance dose of 120 mg daily. The maintenance dose may be administered as a single dose or as 60 mg every 12 hours.
In the management of more severe infections (particularly chronic infections of the urinary tract), 120 mg every 12 hours is recommended.
For certain selected specific indications, the recommended duration or dosage and duration of DORYX MPC in adult patients are as follows:
1. Streptococcal infections, therapy should be continued for 10 days.
2. Uncomplicated urethral, endocervical, or rectal infection caused by C. trachomatis: 120 mg, by mouth, twice-a-day for 7 days.
3. Uncomplicated gonococcal infections in adults (except anorectal infections in men): 120 mg, by mouth, twice-a-day for 7 days. As an alternate single visit dose, administer 360 mg followed in one hour by a second 360 mg dose.
4. Nongonococcal urethritis (NGU) caused by C. trachomatis and U. urealyticum: 120 mg, by mouth, twice-a-day for 7 days.
5. Syphilis – early: Patients who are allergic to penicillin should be treated with doxycycline 120 mg, by mouth, twice-a-day for 2 weeks.
6. Syphilis of more than one year’s duration: Patients who are allergic to penicillin should be treated with doxycycline 120 mg, by mouth, twice-a-day for 4 weeks.
7. Acute epididymo-orchitis caused by N. gonorrhoeae: 120 mg, by mouth, twice-a-day for at least 10 days.
8. Acute epididymo-orchitis caused by C. trachomatis: 120 mg, by mouth, twice-a-day for at least 10 days

Dosage In 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 of DORYX MPC is 2.6 mg per kg of body weight administered every 12 hours. Pediatric patients weighing 45 kg or more should receive the adult dose.
For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dosage schedule of DORYX MPC is 5.3 mg per kg of body weight divided into two doses on the first day of treatment, followed by a maintenance dose of 2.6 mg per 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.

Dosage For Prophylaxis Of Malaria

For adults, the recommended dose of DORYX MPC is 120 mg daily.

For pediatric patients 8 years of age and older, the recommended dosage of DORYX MPC is 2.4 mg per kg of body weight administered once daily. Pediatric patients weighing 45 kg or more should receive the adult dose.

Prophylaxis should begin 1 or 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.

Dosage For Inhalational Anthrax (Post-Exposure)

For adults, the recommended dosage is 120 mg, of DORYX MPC, by mouth, twice-a-day for 60 days.

For pediatric patients weighing less than 45 kg, the recommended dosage of DORYX MPC is 2.6 mg per kg of body weight, by mouth, twice-a-day for 60 days. Pediatric patients weighing 45 kg or more should receive the adult dose.

Contraindications

DORYX MPC is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines.

Special warnings and precautions for use

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Tooth Development

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 DORYX MPC 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

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including DORYX MPC Tablets, 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 antibacterial 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 antibacterial use 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.

Photosensitivity

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.

Potential For Microbial Overgrowth

DORYX MPC may result in overgrowth of non-susceptible organisms, including fungi. If such infections occur, discontinue use and institute appropriate therapy.

Intracranial Hypertension

Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracycline including DORYX MPC. 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. Avoid concomitant use of isotretinoin and DORYX MPC 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.

Skeletal Development

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..

Antianabolic Action

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.

Malaria

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.

Development Of Drug-Resistant Bacteria

Prescribing DORYX MPC in the absence of a 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.

Laboratory Monitoring For Long-Term Therapy

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

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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

Use In Specific Populations

Pregnancy

Risk Summary

There are no adequate 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.¹ In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively [see Data].

Clinical Considerations

Embryo/Fetal Risk

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 also 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 the potential hazard to the fetus..

Data

Human Data

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.²

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.³

Lactation

Risk Summary

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 contraindicated. The effects of prolonged exposure to doxycycline on breast milk production and breast fed neonates, infants and children are unknown.⁴ The developmental and health benefits of breast feeding should be considered along with the mother’s clinical need for DORYX MPC and any potential adverse effects on the breast fed child from DORYX MPC or from the underlying maternal condition.

Pediatric Use

Because of the effects of drugs of the tetracycline-class on tooth development and growth, use DORYX MPC 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.

Geriatric Use

Clinical studies of DORYX MPC 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. DORYX MPC Tablets each contain less than 10 mg of sodium.

REFERENCES

1. Friedman JM, Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS). Baltimore, MD: The Johns Hopkins University Press: 2000: 149-195. The TERIS (Teratogen Information System) is available at: http://www.micromedexsolutions.com/ (cited: 2016 Jan).

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. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); [Last Revision Date 2015 March 10; cited 2016 Jan]. Doxycycline; LactMed Record Number: 100; [about 3 screens]. Available from: http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm

Interaction with other medicinal products and other forms of interaction

SIDE EFFECTS

The following adverse reactions have been identified during post-approval use of doxycycline. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Due to oral doxycycline’s virtually complete absorption, side effects to 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. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Esophagitis and esophageal ulcerations have been reported in patients receiving capsule and tablet forms of drugs in the tetracycline-class. Most of these patients took medications immediately before going to bed.

Skin: Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, and erythema multiforme have been reported. Photosensitivity is discussed above.

Renal: Rise in BUN has been reported and is apparently dose-related.

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.

Intracranial Hypertension: Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracycline

Thyroid Gland Changes: When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function are known to occur.

DRUG INTERACTIONS

Anticoagulant Drugs

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

Penicillin

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

Antacids And Iron Preparations

Absorption of tetracyclines including DORYX MPC is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron-containing preparations.

Oral Contraceptives

Concurrent use of tetracyclines, including DORYX MPC may render oral contraceptives less effective.

Barbiturates And Anti-Epileptics

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

Penthrane

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

Drug/Laboratory Test Interactions

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

Fertility, pregnancy and lactation

Risk Summary

There are no adequate 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.¹ In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively [see Data].

Clinical Considerations

Embryo/Fetal Risk

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 also 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 the potential hazard to the fetus..

Data

Human Data

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.²

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.³

Undesirable effects