Doxycin Cap 100mg Product Monograph

Recent Major Label Changes

None at time of the most recent authorization.

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ................................................................................................................ 2

Table of Contents ................................................................................................................................. 2

Part 1: Healthcare Professional Information ......................................................................................... 4

1. 1.

   Indications ............................................................................................................................... 4

   1.1. Pediatrics ............................................................................................................................. 5

   1.2. Geriatrics ............................................................................................................................. 5

2. 2. Contraindications ..................................................................................................................... 5
3. 4.

   Dosage and Administration ...................................................................................................... 5

   4.2. Recommended Dose and Dosage Adjustment .................................................................... 5

   4.4. Administration ..................................................................................................................... 6

   4.5. Missed Dose ........................................................................................................................ 6

4. 5. Overdose ................................................................................................................................. 6
5. 6. Dosage Forms, Strengths, Composition, and Packaging ............................................................ 6
6. 7.

   Warnings and Precautions ........................................................................................................ 7

   General ............................................................................................................................................. 7

   Carcinogenesis and Genotoxicity ..................................................................................................... 7

   Gastrointestinal ................................................................................................................................ 7

   Genitourinary ................................................................................................................................... 8

   Hepatic/Biliary/Pancreatic ............................................................................................................... 8

   Immune ............................................................................................................................................ 8

   Monitoring and Laboratory Tests ..................................................................................................... 8

   Neurologic ........................................................................................................................................ 9

   Renal ................................................................................................................................................. 9

   Sensitivity/Resistance ....................................................................................................................... 9

   Skin ................................................................................................................................................... 9

   7.1. Special Populations ............................................................................................................. 9

   7.1.1. Pregnancy ..................................................................................................................... 9

   7.1.2. Breastfeeding ............................................................................................................. 10

   7.1.3. Pediatrics .................................................................................................................... 10

   7.1.4. Geriatrics .................................................................................................................... 10

7. 8.

   Adverse Reactions ................................................................................................................... 10

   8.1. Adverse Reaction Overview .............................................................................................. 10

8. 9.

   Drug Interactions .................................................................................................................... 11

   9.3. Drug-Behaviour Interactions ............................................................................................. 11

   9.4. Drug-Drug Interactions ...................................................................................................... 12

   9.5. Drug-Food Interactions ..................................................................................................... 13

   9.6. Drug-Herb Interactions ..................................................................................................... 13

   9.7. Drug-Laboratory Test Interactions .................................................................................... 13

9. 10.

   Clinical Pharmacology ............................................................................................................. 13

   10.1. Mechanism of Action ........................................................................................................ 13

   10.3. Pharmacokinetics .............................................................................................................. 14

10. 11. Storage, Stability, and Disposal ............................................................................................... 16

Part 2: Scientific Information ............................................................................................................... 17

1. 13. Pharmaceutical Information .................................................................................................... 17
2. 14. Clinical Trials ........................................................................................................................... 17
3. 15. Microbiology ........................................................................................................................... 17
4. 16. Non-Clinical Toxicology ........................................................................................................... 18
5. 17. Supporting Product Monographs ............................................................................................. 21

Patient Medication Information .......................................................................................................... 22

Part 1: Healthcare Professional Information

1. Indications

DOXYCIN CAPSULES (doxycycline hyclate capsules) / DOXYCIN TABLETS (doxycycline hyclate tablets) may be indicated for the treatment of:

• Pneumonia

  Single and multilobe pneumonia and bronchopneumonia due to susceptible strains of Streptococcus pneunomiae and other Streptococcus spp., Staphylococcus spp., H. influenzae and Klebsiella pneumoniae.

• Other Respiratory Tract Infections

  Pharyngitis, tonsillitis, sinusitis, otitis media, bronchitis caused by susceptible strains of β-hemolytic Streptococcus, Staphylococcus spp., Streptococcus pneunomiae and H. influenzae.

• Genitourinary Tract Infections

  Pyelonephritis, cystitis, urethritis caused by susceptible strains of Klebsiella spp., Enterobacter aerogenes, E. coli, Enterococcus spp., Staphylococcus spp., Streptococcus spp. and gonococcal urethritis caused by Neisseria gonorrhoeae.

  In adult patients with urethritis, cervicitis and vaginitis with a positive test for Chlamydia trachomatis and/or Ureaplasma urealyticum, clinical resolution and absence of detectable organisms have only been observed at completion of ORAL therapy with doxycycline. Relapses or reinfection can occur. In these cases, limited data suggest that some patients may derive clinical benefit from an alternative therapy. The effect on long term morbidity has not been established.

• Skin and Soft Tissue Infections

  Impetigo, furunculosis, cellulitis, abscess, wound infections, paronychia, caused by susceptible strains of Staphylococcus aureus and epidermidis, Streptococcus spp., E. coli, Klebsiella spp. and Enterobacter aerogenes.

• Gastro-intestinal Infections

  Caused by susceptible strains of Shigella spp., Salmonella spp. and E. coli.

Up to 44 percent of strains of Streptococcus pyogenes and 74 percent of Streptococcus faecalis have been found to be resistant to tetracycline drugs.

Appropriate culture and susceptibility studies should be carried out prior to initiation of therapy with DOXYCIN CAPSULES / DOXYCIN TABLETS and if clinically indicated during treatment. Consideration may be given to the initiation of therapy before obtaining results of these tests, however modification of such treatment may be required once the results become available.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of DOXYCIN CAPSULES / DOXYCIN TABLETS and other antibacterial drugs, DOXYCIN CAPSULES / DOXYCIN TABLETS should be used only to treat 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.

1.1. Pediatrics

Pediatrics (< 8 Years): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of doxycycline hyclate capsules / doxycycline hyclate tablets in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use (7.1.3. Pediatrics).

1.2. Geriatrics

Geriatrics (> 65 Years): No data specific to the geriatric population are available to Health Canada.

2. Contraindications

DOXYCIN CAPSULES / DOXYCIN TABLETS is contraindicated in:

• patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container or to any other tetracycline. For a complete listing, see 6. Dosage Forms, Strengths, Composition, and Packaging.
• patients with myasthenia gravis.
• patients taking isotretinoin (see 7. Warnings and Precautions, Neurologic and 9.4. Drug-Drug Interactions).

4. Dosage and Administration

4.2. Recommended Dose and Dosage Adjustment

EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE EFFECTS.

Adults

The recommended dosage of oral DOXYCIN CAPSULES / DOXYCIN TABLETS for the majority of susceptible infections is a single loading dose of 200 mg on the first day of treatment followed by a maintenance dosage of 100 mg once daily at the same time each day thereafter.

In the management of more severe infections (particularly chronic infections of the urinary tract), 200 mg should be given daily throughout the treatment period.

Therapy should be continued for at least 24 to 48 hours after symptoms and fever have subsided. It should be noted, however, that effective antibacterial levels are usually present 24 to 36 hours following discontinuance of DOXYCIN CAPSULES / DOXYCIN TABLETS therapy.

When used in streptococcal infections, therapy should be continued for 10 days to prevent the development of rheumatic fever or glomerulonephritis.

For treatment of uncomplicated acute gonococcal infections, the recommended dosage is 200 mg starting and 100 mg in the evening, the first day, followed by 100 mg b.i.d. for 3 days.

For treatment of uncomplicated urethral, endocervical, or vaginal infections in adults associated with Chlamydia trachomatis and Ureaplasma urealyticum: 100 mg, by mouth, twice a day for at least 10 days.

No alteration in recommended dosage schedule need be made when treating patients with impaired renal function.

4.4. Administration

DOXYCIN CAPSULES and DOXYCIN TABLETS should be given with or after a meal in order to minimize the possibility of gastric upset. Antacids and iron preparations impair absorption and should not be given concomitantly to patients taking oral DOXYCIN CAPSULES / DOXYCIN TABLETS.

Patients should be advised to take DOXYCIN CAPSULES and DOXYCIN TABLETS with a full glass of water, to keep in orthostatic position after the administration and not to go to bed within 1 to 2 hours after the intake.

4.5. Missed Dose

If a dose of this medication is missed, the patient should take it as soon as they remember. But if it is almost time for their next dose, the missed dose can be skipped, and the patient can continue with the next scheduled dose. The patient should go back to the regular dosing schedule; they should not take two doses at the same time.

5. Overdose

Specific information on symptoms or treatment of overdosage with doxycycline hyclate is not available. In case of overdosage, discontinue medication. Treatment, therefore, should be symptomatic and gastric lavage may be considered for overdosage with the oral preparation. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.

1. 6. Dosage Forms, Strengths, Composition, and Packaging

Table 1 – Dosage Forms, Strengths, and Composition

Availability

DOXYCIN CAPSULES 100 mg are available as aqua-blue hard gelatin capsules, printed "H" or "539" in black on the head and "H" or "539" in black on the body. Available in bottles of 100 capsules.

DOXYCIN TABLETS 100 mg are available as orange, round, biconvex film-coated tablets, engraved “DOXYCIN 100” on one side and scored on the other side. Available in bottles of 100 and 300 tablets.

7. Warnings and Precautions

General

Doxycycline hyclate like other tetracyclines, may form a stable calcium complex in any bone-forming tissue, though in vitro it binds calcium less strongly than other tetracyclines. It should be anticipated that the use of DOXYCIN CAPSULES / DOXYCIN TABLETS during tooth development (last trimester of pregnancy, during lactation, neonatal period and early childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). Though more commonly associated with long term use of tetracyclines, this effect has also been known to occur after short courses. Enamel hypoplasia has also been reported.

DOXYCIN CAPSULES / DOXYCIN TABLETS should, therefore, not be used in these age groups unless other drugs are unlikely to be effective or are contraindicated.

Carcinogenesis and Genotoxicity

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).

Gastrointestinal

Instances of esophageal lesions (esophagitis and ulcerations), sometimes severe, have been reported in patients receiving doxycycline. The patients must be instructed to take DOXYCIN CAPSULES / DOXYCIN TABLETS with a full glass of water, to keep in orthostatic position after the administration and not to go to bed within 1 to 2 hours after the intake. If symptoms such as dysphagia and retrosternal pain occur, DOXYCIN CAPSULES / DOXYCIN TABLETS should be discontinued and an esophagic lesion must be investigated (see 8.1. Adverse Reaction Overview). DOXYCIN CAPSULES / DOXYCIN TABLETS should not be prescribed to patients with obstructive esophagic pathology, such as stenosis and achalasia.

Cases of esophageal injury consisting of esophagitis and esophageal ulceration have been reported in patients receiving doxycycline hyclate orally. Most of these patients took medication immediately before going to bed and/or without adequate amount of fluid (see 4.2. Recommended Dose and Dosage Adjustment). If this should occur, DOXYCIN CAPSULES / DOXYCIN TABLETS should be discontinued until healing occurs. Administration of antacids and/or cimetidine has provided relief in the treatment of such cases. TO REDUCE THE RISK OF ESOPHAGEAL INJURY, PATIENTS SHOULD BE ADVISED TO TAKE DOXYCIN CAPSULES OR DOXYCIN TABLETS WITH AN ADEQUATE AMOUNT OF FLUID WHILE STANDING OR SITTING UPRIGHT. DOXYCIN CAPSULES / DOXYCIN TABLETS should not be given at bedtime.

Clostridium difficile-associated disease (CDAD) has been reported with use of many antibacterial agents, including doxycycline hyclate. CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of colon subsequent to the administration of any antibacterial agent. CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridium difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy.

If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against Clostridium difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against Clostridium difficile. Surgical evaluation should be instituted as clinically indicated, as surgical intervention may be required in certain severe cases (see 8.1. Adverse Reaction Overview).

Genitourinary

Patients should be advised that the use of doxycycline might increase the incidence of vaginal candidiasis (see 8.1. Adverse Reaction Overview).

Hepatic/Biliary/Pancreatic

Concurrent administration of DOXYCIN CAPSULES / DOXYCIN TABLETS with agents known to be hepatotoxic should be avoided.

Immune

Hypersensitivity

Hypersensitivity adverse drug reactions that included, but not limited to anaphylactic reaction, angioedema, dyspnea, tachycardia, hypotension, pericarditis, urticaria, rash, erythema multiforme, Stevens-Johnson and toxic epidermal necrolysis have been reported with doxycycline hyclate capsules / doxycycline hyclate tablets use. Some of these reactions were serious. If an allergic reaction occurs, administration of DOXYCIN CAPSULES / DOXYCIN TABLETS should be discontinued and appropriate therapy should be initiated.

Doxycycline hyclate capsules / doxycycline hyclate tablets has been associated with the development of autoimmune adverse drug reactions including exacerbation of systemic lupus erythematous, rash, peripheral edema, arthralgia, myalgia, serum sickness. If patients with autoimmune reactions are suspected, administration of DOXYCIN CAPSULES / DOXYCIN TABLETS should be discontinued and liver function tests, ANA, CBC, and other appropriate tests should be performed to evaluate the patients.

Monitoring and Laboratory Tests

In long term therapy with DOXYCIN CAPSULES / DOXYCIN TABLETS, periodic laboratory evaluation of organ systems, including hematopoietic, renal and hepatic studies should be performed. Liver function tests should be carried out at regular intervals on patients receiving high doses for prolonged periods of time.

Neurologic

Benign intracranial hypertension (pseudotumor cerebri) has been associated with the use of tetracyclines including doxycycline. Benign intracranial hypertension (pseudotumor cerebri) is usually transient, however cases of permanent visual loss secondary to benign intracranial hypertension (pseudotumor cerebri) have been reported with tetracyclines including doxycycline. 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. Concomitant use of isotretinoin and doxycycline should be avoided because isotretinoin is also known to cause benign intracranial hypertension (pseudotumor cerebri) (see 8.1. Adverse Reaction Overview).

Renal

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

In clinical studies to date, administration of doxycycline hyclate did not lead to increased serum levels nor to an increase in the serum half-life of doxycycline in patients with impaired renal function. Modification of doxycycline hyclate dosage for these patients is not necessary. Although no evidence of increased toxicity has been observed in such patients, the potential for increased hepatic or other toxicity should be considered until further data on the metabolic fate of doxycycline under these conditions become available.

Sensitivity/Resistance

Prescribing DOXYCIN CAPSULES / DOXYCIN TABLETS in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.

The use of antibiotics may occasionally result in overgrowth of non-susceptible organisms including fungi; thus, observation of the patient is essential.

Skin

Photosensitivity reaction 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 DOXYCIN CAPSULES / DOXYCIN TABLETS, and treatment should be discontinued at the first evidence of skin erythema (see 8.1. Adverse Reaction Overview). The use of sunscreen or sunblock prior to sun or UV light exposure should be considered in patients taking DOXYCIN CAPSULES / DOXYCIN TABLETS.

7.1. Special Populations

7.1.1. Pregnancy

DOXYCIN CAPSULES / DOXYCIN TABLETS should not be administered to pregnant women, unless in the judgment of the physician the potential benefit to the mother outweighs the risk to the fetus (see above 7. Warnings and Precautions, General section about use during tooth development).

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.

7.1.2. Breastfeeding

Tetracyclines are excreted in the milk of lactating women. Accordingly, the use of DOXYCIN CAPSULES / DOXYCIN TABLETS is not recommended in women while they are breast feeding (see above 7. Warnings and Precautions, General section about use during tooth development).

7.1.3. Pediatrics

Pediatrics (< 8 years): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of doxycycline hyclate capsules / doxycycline hyclate tablets in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use (see above 7. Warnings and Precautions, General section about use during tooth development).

Doxycycline hyclate like other tetracyclines forms a stable calcium complex in any bone-forming tissue. A decrease in the 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.

7.1.4. Geriatrics

See 1.2. Geriatrics.

8. Adverse Reactions

8.1. Adverse Reaction Overview

Blood and lymphatic system disorders: Hemolytic anemia, thrombocytopenia, neutropenia, eosinophilia, leukopenia.

Cardiac disorders: Pericarditis, tachycardia.

Ear and labyrinth disorders: Tinnitus.

Endocrine disorders: When given over prolonged periods tetracyclines have been reported to produce brown-black microscopic discolouration of the thyroid gland. Abnormalities of thyroid function have not been shown to date (see 16. Non-Clinical Toxicology).

Gastrointestinal disorders: As with other broad spectrum antibiotics administered orally and parenterally, gastro-intestinal disturbances such as nausea, vomiting, diarrhea, glossitis, dysphagia, stomatitis, proctitis and enterocolitis, may occur, but have rarely been sufficiently troublesome to warrant discontinuation of therapy with doxycycline hyclate. Abdominal pain, dyspepsia (heartburn/gastritis), pseudomembranous colitis, Clostridium difficile colitis and inflammatory lesions (with monilial overgrowth) in the anogenital region have also been reported. Due to oral doxycycline’s virtually complete absorption, side effects of the lower bowel, particularly diarrhea, have been infrequent.

Cases of esophagitis and esophageal ulcer, sometimes severe, in patients receiving capsule and tablet form of doxycycline hyclate have been reported (see 7. Warnings and Precautions, Gastrointestinal and 4.2. Recommended Dose and Dosage Adjustment).

General disorders and administration site conditions: Peripheral edema.

Hepatobiliary disorders: There have been reports of hepatotoxicity (including hepatic failure, autoimmune hepatitis and cholestasis) and hepatic function abnormal. As with other tetracyclines, hepatitis, elevation of SGOT or SGPT values have been reported, the significance of which is not known.

Immune system disorders

Hypersensitivity

Hypersensitivity reactions consisting of anaphylactic reaction, anaphylactoid reaction, and serum sickness, have been reported.

Infections and infestations: Vaginal candidiasis (see 7. Warnings and Precautions, Genitourinary).

Investigations: Renal Function Analysis - Blood urea increased (apparently dose related) has been reported.

Metabolism and nutrition disorders: Decreased appetite.

Musculoskeletal and connective tissue disorders: Exacerbation of systemic lupus erythematosus, arthralgia, myalgia.

Nervous system disorders: Headache, fontanelle bulging in infants and benign intracranial hypertension (pseudotumor cerebri) in adults. In relation to benign intracranial hypertension, symptoms included blurring of vision, scotomata and diplopia. Permanent visual loss has been reported (see 7. Warnings and Precautions, Neurologic).

Psychiatric disorders: Depression, anxiety, suicidal ideation, insomnia, abnormal dreams, hallucination.

Respiratory, thoracic and mediastinal disorders: Dyspnea

Skin and subcutaneous tissue disorders:

Skin reactions, such as maculopapular and erythematous rashes, exfoliative dermatitis, erythema multiforme, photosensitivity reaction, photo-onycholysis, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, angioedema, Henoch-Schonlein Purpura and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving doxycycline. Fixed drug eruptions have occurred with doxycycline and have been associated with worsening severity upon subsequent administrations, including generalized bullous fixed drug eruption.

If severe skin reactions occur, discontinue doxycycline immediately and institute appropriate therapy.

Vascular disorders: Flushing, hypotension.

9. Drug Interactions

9.3. Drug-Behaviour Interactions

Alcohol

The concurrent use of doxycycline hyclate with alcohol has been reported to reduce the plasma half-life of doxycycline, which may diminish its antimicrobial effectiveness. This effect can persist for several days after discontinuation of therapy with the interacting agent. Therefore, when DOXYCIN CAPSULES or DOXYCIN TABLETS are administered together with alcohol or with drugs known to induce enzymes, consideration should be given to adjusting the daily dose accordingly.

9.4. Drug-Drug Interactions

Table 2 – Established or Potential Drug-Drug Interactions

Legend: T = Theoretical

9.5. Drug-Food Interactions

Although a significant drug-food interaction has not been observed, for safety/tolerability reasons, this drug should be taken with food as recommended in 4.4. Administration.

9.6. Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7. Drug-Laboratory Test Interactions

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

10. Clinical Pharmacology

10.1. Mechanism of Action

Doxycycline hyclate is a broad-spectrum antibiotic and is active against a wide range of Gram-negative and Gram-positive organisms. Doxycycline exerts its bacteriostatic effect by the inhibition of protein synthesis.

10.3. Pharmacokinetics

Serum levels of doxycycline administered orally follow a similar pattern to those obtained with equivalent dosages administered intravenously as shown in Table 3. Peak serum levels were slightly higher and occurred earlier following intravenous administration than for oral administration (see Table 3).

Table 3 - Serum levels of doxycycline administered orally Vs I.V.

Serum levels (mg/L) after oral and I.V. infusion over 60 minutes (0.5 mg/mL) of a total daily dose of 200 mg of doxycycline hyclate on the first day (100 mg every 12 hours) and a dose of 100 mg on the second and third day of administration (22 Male Volunteers/Group).

Where no p is stated, p>.10

— time of dosing

Absorption

Doxycycline was rapidly and almost completely absorbed following oral administration. The absorption of doxycycline was not significantly influenced by ingestion of food or milk (see Table 4).

Table 4 - Effect of Food or Milk on Absorption of a Single Oral Dose of Doxycycline 100 mg as Hyclate (5 Male Volunteers/Group).

Distribution

Doxycycline is approximately 93% protein bound. The volume of distribution is approximately 0.7 L/kg.

Metabolism

The serum half-life of doxycycline is 18 hours. The serum half-life of doxycycline is not increased, nor does it accumulate in the blood of patients with impaired renal function.

Elimination

Doxycycline is excreted in the urine (approximately 35 to 40% of the administered dose) and in the bile. Hemodialysis does not alter the serum half-live. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with normal renal function (creatinine clearance about 75 mL/min.). This percentage excretion may fall to a range as low as 1 to 5%/72 hours in individuals with severe renal insufficiency (creatinine clearance below 10 mL/min.).

Special populations and conditions

• Pediatrics See 7.1.3. Pediatrics.
• Pregnancy and breastfeeding See 7.1.1. Pregnancy and 7.1.2. Breastfeeding.
• Storage, Stability, and Disposal

Bottles of DOXYCIN CAPSULES and DOXYCIN TABLETS 100 mg should be stored at controlled room temperature (15-30°C), protected from light and excessive humidity.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance(s): Doxycycline Hyclate.

Chemical Name:2-Naphthacenecarboxamide, 4-(dimethyIamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6- methyl-1,11-dioxo- monohydrochloride, compd. with ethanol (2:1), monohydrate, |4S-(4α,4aα,5α,5aα,6α,12α) | -or α-6-deoxy-5-oxytetracycline.

Molecular formula and molecular mass: (C₂₂H₂₄N₂O₈.HCl)₂.C₂H₆O.H₂O and 1025.89 g/mol.

Structural Formula:

Physicochemical properties: Doxycycline hyclate is a yellow crystalline powder with a slight ethanolic odour and a bitter taste. The melting point is about 200°C with decomposition. It is soluble in a 1 in 3 dilution with water, 1 in 60 with alcohol and 1 in 4 with methyl alcohol; slightly soluble in chloroform and ether; soluble in solutions of alkali hydroxides and carbonates.

14. Clinical Trials

The clinical trial data on which the original indication was authorized is not available.

15. Microbiology

Doxycycline is a broad spectrum antibiotic and has been shown to be active in vitro against the following Gram-negative, Gram-positive and other micro-organisms:

Staphylococcus aureus

Staphylococcus epidermidis (albus)

Streptococcus pyogenes

Streptococcus faecalis

Streptococcus pneumoniae

Streptococcus viridans

Listeria monocytogenes

Klebsiella pneumoniae

Salmonella typhi

Salmonella typhimurium

Salmonella enteriditis

Shigella sonnei

Shigella flexneri

Corynebacterium diphtheriae

Bacillus subtilis

Neisseria gonorrhoeae

Neisseria catarrhalis

Escherichia coli

Enterobacter aerogenes

Pseudomonas aeruginosa

Haemophilus influenzae

Serratia spp.

Brucella spp.

Proteus spp.

Pasteurella spp.

Mycoplasma pneumoniae

Chlamydia trachomatis

Ureaplasma urealyticum

Bacillus anthracis

The drugs in the tetracycline class have closely similar antimicrobial spectra, and cross-resistance among them is common.

SUSCEPTIBILITY TESTING

The Kirby-Bauer method of disc susceptibility testing (using the 30 mcg doxycycline disc) and dilution susceptibility should be interpreted according to the criteria in Table 5.

16. Non-Clinical Toxicology

General toxicology

Doxycycline Hyclate

1. a) Acute Toxicity

The acute oral and parenteral toxicity of doxycycline in mice, rats and dogs are as follows:

The intraperitoneal LD₅₀'s of doxycycline in weanling and newborn rats are 262 (222 to 309) and 300 (275 to 327) mg/kg, respectively.

1. b) Subacute Toxicity

One to 2½ - month subacute toxicity studies were conducted in rats, hamsters, dogs and monkeys. Doxycycline induced a yellow fluorescence (under ultraviolet light) of bone, teeth, kidney and/or liver, in all animal species tested. In rats, doxycycline produced no toxic effects in doses of up to 500 mg/kg/day for 30 days. In hamsters, doxycycline in dosages of 500 or 250 mg/kg/day produced weight loss and early death, but the 50 mg/kg level (for 30 days) was nontoxic. In dogs, doxycycline in dosages of 250 mg/kg/day for one month produced discoloration of the thyroid gland with the presence of intracytoplasmic granules in follicular acini and occasional amorphous body formation within follicular colloid.

Certain biochemical, functional and histological changes of the liver occurred in the dogs (but not in the rats, hamsters, or monkeys) receiving doxycycline for 30 days at dosage levels of 250 and 50 mg/kg/day, but not at the 25 mg/kg/day level. The biochemical changes in the blood were elevations of alkaline phosphatase, SGPT and/or BSP retention. Histologic changes were confined to bile ductular proliferation and hepatocellular intracytoplasmic inclusion bodies and Kupffer cells swollen with PAS-positive granular material. These changes in the dog were reversible upon drug withdrawal.

Monkeys which received doxycycline at dosages of 25 and 50 mg/kg/day for 1 ½ to 2 ½ months showed mild yellow ultraviolet fluorescence of liver, kidney and bone, and the presence of small amounts of intracytoplasmic granular material in the thyroid gland.

1. c) Chronic Toxicity

In an 18-month chronic toxicity study, rats were fed diets containing doxycycline at levels to provide daily drug intake of 500, 250, 50 and 0 mg/kg. Slight depression of weight gains in some rats receiving the 500 mg/kg/day dose occurred during the middle third of the study. The usual yellow ultraviolet fluorescence of bone, teeth and/or kidneys was seen in rats receiving all levels of doxycycline for 6, 12 or 18 months. Dark to light brown discoloration of the thyroid gland was also noted in rats receiving doxycycline for 12 months at levels of 500 and 250 mg/kg/day, and at 18 months at all levels. The only other change noted was depletion of hepatic glycogen in four rats receiving the highest dose level for 12 months.

Beagle dogs received doxycycline at levels of 10 and 100 mg/kg, six days per week. Moderate to marked elevations of alkaline phosphatase and SGPT (occasionally SGOT) were observed in animals receiving doxycycline, 100 mg/kg/day. One of two dogs receiving doxycycline, 100 mg/kg/day, displayed mild bile ductular proliferation and hepatocellular inclusion bodies after 5 months (biopsy sample) and 12 months (necropsy sample). Administration of doxycycline for 5 and 12 months at a level of 100 mg/kg/day and for 12 months at a level of 10 mg/kg caused black and brownish discoloration of the thyroid gland, respectively, with intracytoplasmic granules. Other changes included vasodilatation and focal areas of necrosis of the mucosa of the pyloric and fundic stomach of dogs, and yellow ultraviolet fluorescence of teeth and bones of animals at 100 mg/kg/day dose levels of doxycycline.

Additional groups of 4 beagles each received doxycycline in dosages of 5, 1 and 0 mg/kg/day for 6 months. The only abnormal findings were slight elevations of SGPT values in 3 dogs at the 5 mg/kg level at 180 days.

In a one year chronic toxicity study, groups of four rhesus monkeys each received doxycycline in oral doses of 0, 5, 25 and 50 mg/kg/day, respectively. Oral dosage of 100 mg/kg produced severe gastrointestinal symptoms, e.g., vomiting and diarrhea. In one out of 4 monkeys receiving the 50 mg/kg/day dose, occasional anorexia and diarrhea were observed during the first six months.

Significant pathologic changes noted in monkeys sacrificed after receiving doxycycline for 1 year at dose levels of 50 mg/kg/day were: 1) grossly, very light brown discoloration of the thyroid gland in one of the four monkeys, and 2) microscopically, brownish intracytoplasmic inclusions in the acinar cells of thyroid follicles of three out of four monkeys. Bone and dentin exhibited slight to moderate ultraviolet fluorescence.

Two monkeys, in another study, receiving the 25 mg/kg/day dosage, were sacrificed after 6 and 8 months on test, respectively. Significant gross and histopathologic findings were slight yellow ultraviolet fluorescence of the endosteum and periosteum of bone, and microscopic appearance of small amounts of granular intracytoplasmic material in the acinar cells of thyroid follicles.

The highlights of the chronic toxicity studies can be summarized as follows:

1. 1) Discoloration of the thyroid gland, with deposition of intracytoplasmic granules in the acinar cells of the follicle. Thyroid function, however, did not seem to be affected. This phenomenon appears to be a
2. result of the interaction of the antibiotic with the active iodinating system of the gland.
3. 2) Yellow staining of bones and teeth, which is thought to be due to formation of a tetracycline-calcium-phosphate complex.

Otherwise doxycycline was well tolerated by the rat and monkey at doses up to and including 500 and 50 mg/kg/day for 18 and 12 months, respectively. In dogs, however, repeated daily oral administration of large doses of doxycycline resulted in certain hepatic functional and histopathologic changes which are reversible after drug withdrawal. No adverse hepatic effects were noted in the hamster (1 month), rats (18 months) or monkeys (12 months) for doses up to and including 500, 500 and 50 mg/kg/day, respectively. In view of this and in view of the lack of notable toxicity in our wide human clinical program, it is our opinion that this is a species specific phenomenon, for the dog only.

Doxycycline Monohydrate

With bulk doxycycline monohydrate administered in a 10% aqueous suspension, the oral LD₅₀ for albino male mice was greater than 5000 mg/kg.

Doxycycline Hyclate with Ascorbic Acid

Studies in mice and rats showed the LD₅₀ of doxycycline (as hyclate) I.V. to be 75 mg/kg in mice and 88 mg/kg in rats of doxycycline (using a preparation of doxycycline hyclate equivalent to 100 mg of doxycycline with 480 mg of ascorbic acid as a sterile powder).

No signs of drug toxicity were seen in dogs receiving 20 to 21 daily doses of doxycycline (as hyclate) I.V. at a dose level of 5 mg/kg when administered as a 0.5% solution at a rate of 1 mg/kg/min. Dogs receiving 14, 16 or 17 daily intravenous doses of 10 mg doxycycline (as hyclate) I.V. per kg of bodyweight, or 4 daily 60 minute infusions of 300 mg doxycycline (as hyclate) I.V., or 300 mg degraded doxycycline (as hyclate) I.V. evidenced serum alkaline phosphatase and serum glutamic pyruvic transaminase elevations. No morphological basis for these enzyme elevations was established although moderate bile ductular proliferation was seen in 1 of 2 dogs receiving 4 daily intravenous infusions of degraded doxycycline (as hyclate) I.V.

In 8 dogs receiving daily intravenous doses of 10 mg doxycycline (as hyclate) I.V./kg/day (0.5% solution), 5 of 24 vessels used for injections evidenced degrees of thrombosis with recanalization.

Thrombosis in 3 of 6 sites occurred in 2 dogs receiving infusions of degraded doxycycline (as hyclate) I.V. (30 mg/kg to 0.5% solution). Injection site thrombosis did not occur in 6 dogs (18 sites) receiving daily doses of 5 mg doxycycline (as hyclate) I.V. /kg bodyweight administered as a 0.5% solution at a rate of 1 mg/kg/min (approximately 1 mL/min).

Studies to date indicate that the maximum tolerated intravenous daily dose of doxycycline (as hyclate) I.V. in dogs for 21 consecutive days is 5 mg/kg/day when administered as a 0.5% solution at a rate of 1 mg/kg/min.

Reproduction and developmental toxicology

Doxycycline has no teratologic effects in rats, rabbits or monkeys.

Breeding rats received doxycycline by gavage in doses of 50 and 250 mg/kg/day prior to and throughout two consecutive litters. There was no evidence that doxycycline interfered with the reproductive process in rats.

Pregnant female white New Zealand rabbits received doxycycline orally in doses of 8 and 40 mg/kg/day, respectively, from day 8 to day 16 of pregnancy. Spina bifida and partial anencephaly in one pup each in the control and the 8 mg/kg group, respectively, are believed to be spontaneous and drug-induced.

In teratogenic studies using a limited number of monkeys, doxycycline, in doses ranging from 1 to 50 mg/kg/day, did not produce any teratologic effects.

17. Supporting Product Monographs

1. 1. Vibramycin Capsules, Capsules, 100 mg and Vibra-Tabs Film Coated Tablets, Tablets, 100 mg, control 187868, Product Monograph, Pfizer Canada Inc. (2015-12-22)
2. 2. APO-DOXY, Capsules, 100 mg and APO-DOXY-TABS, Tablets, 100 mg, control 305293, Product Monograph, APOTEX Inc. (2026-06-05)