1.1 Rickettsial Infections

ACTICLATE® and ACTICLATE® CAP are indicated for treatment of Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsial pox, and tick fevers caused by Rickettsiae.

1.2 Sexually Transmitted Infections

ACTICLATE and ACTICLATE CAP are indicated for treatment of the following sexually transmitted infections:

• Uncomplicated urethral, endocervical or rectal infections 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.

1.3 Respiratory Tract Infections

ACTICLATE and ACTICLATE CAP are 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.

1.4 Specific Bacterial Infections

ACTICLATE and ACTICLATE CAP are 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.

ACTICLATE and ACTICLATE CAP are 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.

1.5 Ophthalmic Infections

ACTICLATE and ACTICLATE CAP are 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.

1.6 Anthrax Including Inhalational Anthrax (Post-Exposure)

ACTICLATE and ACTICLATE CAP are indicated for the 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.

1.7 Alternative Treatment for Selected Infections when Penicillin is Contraindicated

ACTICLATE and ACTICLATE CAP are indicted 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.

1.8 Adjunctive Therapy for Acute Intestinal Amebiasis and Severe Acne

In acute intestinal amebiasis, ACTICLATE and ACTICLATE CAP may be a useful adjunct to amebicides.

In severe acne, ACTICLATE and ACTICLATE CAP may be useful adjunctive therapy.

1.9 Prophylaxis of Malaria

ACTICLATE and ACTICLATE CAP are 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 [see Dosage and Administration (2.4) and Patient Counseling Information (17)].

1.10 Usage

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

2.1 Important Administration Instructions

• The usual dosage and frequency of administration of ACTICLATE and ACTICLATE CAP differs from that of the other tetracyclines. Exceeding the recommended dosage may result in an increased incidence of adverse reactions.
• Administer ACTICLATE and ACTICLATE CAP with adequate amounts of fluid to wash down the drugs and reduce the risk of esophageal irritation and ulceration [see Adverse Reactions (6)].
• If gastric irritation occurs, ACTICLATE and ACTICLATE CAP may be given with food or milk [see Clinical Pharmacology (12.3)]
• Swallow ACTICLATE CAP whole. Do not break, open, crush, dissolve or chew the capsule.
• ACTICLATE tablets (150 mg) can be broken into two-thirds or one-third to provide a 100 mg and 50 mg strength, respectively [see FDA-approved patient labeling].

2.2 Dosage in Adult Patients

• The usual dosage of ACTICLATE is 200 mg on the first day of treatment (administered 100 mg every 12 hours) followed by a maintenance dose of 100 mg daily. 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 certain selected specific indications, the recommended duration or dosage and duration of ACTICLATE or ACTICLATE CAP 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 Chlamydia trachomatis: 100 mg by mouth twice-a-day for 7 days.
  3. 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.
  4. Nongonococcal urethritis (NGU) caused by C. trachomatis and U. urealyticum: 100 mg by mouth twice-a-day for 7 days.
  5. Syphilis – early: Patients who are allergic to penicillin should be treated with doxycycline 100 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 100 mg by mouth twice-a-day for 4 weeks.
  7. Acute epididymo-orchitis caused by N. gonorrhoeae: 100 mg by mouth, twice-a-day for at least 10 days.
  8. Acute epididymo-orchitis caused by C. trachomatis: 100 mg, by mouth, twice-a-day for at least 10 days.

2.3 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 ACTICLATE and ACTICLATE CAP is 2.2 mg per kg of body weight administered every 12 hours. Pediatric patients weighing 45 kg or more should receive the adult dose [see Warnings and Precautions (5.1)].
• For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dosage schedule of ACTICLATE and ACTICLATE CAP is 4.4 mg per kg of body weight divided into two doses on the first day of treatment, followed by a maintenance dose of 2.2 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.

2.4 Dosage for Prophylaxis of Malaria

For adults, the recommended dose of ACTICLATE is 100 mg daily.

For pediatric patients 8 years of age and older, the recommended dosage of ACTICLATE and ACTICLATE CAP is 2 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.

2.5 Dosage for Inhalational Anthrax (Post-Exposure)

For adults, the recommended dosage is 100 mg, of ACTICLATE, by mouth, twice-a-day for 60 days.

For pediatric patients weighing less than 45 kg, the recommended dosage of ACTICLATE and ACTICLATE CAP is 2.2 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.

5.1 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 ACTICLATE and ACTICLATE CAP 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.

5.2 Clostridium difficile Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ACTICLATE and ACTICLATE CAP, 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 antibacterial 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.

5.3 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.

5.4 Potential for Microbial Overgrowth

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

5.5 Severe Skin Reactions

Severe skin reactions, such as exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving doxycycline [See Adverse Reactions (6)]. If severe skin reactions occur, doxycycline should be discontinued immediately and appropriate therapy should be instituted.

5.6 Intracranial Hypertension

Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines including ACTICLATE and ACTICLATE CAP. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Concomitant use of isotretinoin and ACTICLATE and ACTICLATE CAP should be avoided because isotretinoin is also known to cause pseudotumor cerebri.

Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize.

5.7 Delayed 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 per kg every six hours. This reaction was shown to be reversible when the drug was discontinued.

Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy. Tetracycline-class drugs can cause fetal harm when administered to a pregnant woman, but data for doxycycline are limited. 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.

5.8 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.

5.9 Incomplete Suppression of 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.

5.10 Development of Drug-Resistant Bacteria

Prescribing ACTICLATE and ACTICLATE CAP 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.

5.11 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.

7.1 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.

7.2 Penicillin

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

7.3 Antacids and Iron Preparations

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

7.4 Oral Contraceptives

Concurrent use of tetracyclines, including ACTICLATE and ACTICLATE CAP may render oral contraceptives less effective.

7.5 Barbiturates and Anti-Epileptics

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

7.6 Penthrane®

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

7.7 Drug and Laboratory Test Interactions

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

8.1 Pregnancy

8.3 Nursing Mothers

Tetracyclines are excreted in human milk, however, the extent of absorption of tetracyclines including doxycycline, by the breastfed infant is not known. Short-term use by lactating women is not necessarily contraindicated. The effects of prolonged exposure to doxycycline in breast milk are unknown4. Because of the potential for serious adverse reactions in nursing infants from doxycycline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother [see Warnings and Precautions (5.1, 5.7)].

8.4 Pediatric Use

Because of the effects of drugs of the tetracycline-class on tooth development and growth, use ACTICLATE and ACTICLATE CAP 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 [see Warnings and Precautions (5.1, 5.7) and Dosage and Administration (2.1, 2.5)].

8.5 Geriatric Use

Clinical studies of doxycycline hyclate tablets 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. ACTICLATE Tablets each contains less than 1 mg of sodium.

12.1 Mechanism of Action

Doxycycline is a tetracycline-class antimicrobial drug [see Microbiology (12.4)].

12.3 Pharmacokinetics

Absorption

ACTICLATE (doxycycline hyclate) Tablets: Following administration of a single 300 mg dose to adult volunteers, average peak plasma doxycycline levels were 3.0 mcg per mL at 3 hours, decreasing to 1.18 mcg per mL at 24 hours. The mean Cmax and AUC0-∞ of doxycycline are 24% and 15% lower, respectively, following single dose administration of ACTICLATE, 150 mg tablets with a high fat meal (including milk) compared to fasted conditions. The clinical significance of these decreases is unknown.

ACTICLATE CAP (doxycycline hyclate) Capsules. Following administration of a single 300 mg dose to adult volunteers, average peak plasma doxycycline levels were 2.8 mcg per mL at 3 hours, decreasing to 1.1 mcg per mL at 24 hours. The mean Cmax of doxycycline is approximately 20% lower and the AUC0-∞ is unchanged following single dose administration of ACTICLATE CAP Capsules with a high fat meal (including milk) compared to fasted conditions. The clinical significance of this decrease in Cmax is unknown.

Excretion

Tetracyclines are concentrated in bile by the liver and excreted in the urine and feces at high concentrations and in a biologically active form.

Excretion of doxycycline by the kidney is about 40% per 72 hours in individuals with a creatinine clearance of about 75 mL per minute. This percentage may fall as low as 1% per 72 hours to 5% per 72 hours in individuals with a creatinine clearance below 10 mL per minute. Studies have shown no significant difference in the serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter the serum half-life.

12.4 Microbiology

Mechanism of Action

Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against a broad range of Gram-positive and Gram-negative bacteria.

Resistance

Cross resistance with other tetracyclines is common.

Antimicrobial Activity

Doxycycline has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)].

Gram-negative bacteria

Acinetobacter species

Bartonella bacilliformis

Brucella species

Campylobacter fetus

Enterobacter aerogenes

Escherichia coli

Francisella tularensis

Haemophilus ducreyi

Haemophilus influenzae

Klebsiella granulomatis

Klebsiella species

Neisseria gonorrhoeae

Shigella species

Vibrio cholerae

Yersinia pestis

Gram-positive bacteria

Bacillus anthracis

Listeria monocytogenes

Streptococcus pneumoniae

Anaerobic bacteria

Clostridium species

Fusobacterium fusiforme

Propionibacterium acnes

Other bacteria

Nocardiae and other aerobic Actinomyces species

Borrelia recurrentis

Chlamydophila psittaci

Chlamydia trachomatis

Mycoplasma pneumoniae

Rickettsiae species

Treponema pallidum

Treponema pallidum subspecies pertenue

Ureaplasma urealyticum

Parasites

Balantidium coli

Entamoeba species

Plasmodium falciparum*

*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 Testing Methods

When available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid in the selection of an appropriate antibacterial drug for treatment.

Dilution techniques:

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs values should be determined using a standardized test method5,6,7,8,9 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table 1.

Diffusion techniques:

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds.

The zone size should be determined using a standardized test method5,7,10. This procedure uses paper disks impregnated with 30 mcg doxycycline to test the susceptibility of bacteria to doxycycline. The disk diffusion interpretive criteria are provided in Table 1.

Anaerobic Techniques:

For anaerobic bacteria, the susceptibility to doxycycline can be determined by a standardized test method5,11. The MIC values obtained should be interpreted according to the criteria provided in Table 1.

Doxycycline susceptibility testing interpretive criteria for anaerobes, Haemophilus influenzae, Mycoplasma pneumoniae, Neisseria gonorrhoeae, and Ureaplasma urealyticum have not been established. Isolates of these species that are susceptible to tetracycline are also considered susceptible to doxycycline.5

A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug product is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test5,6,7,8,9,10,11. Standard doxycycline powders should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 30 mcg doxycycline disk, the criteria noted in Table 2 should be achieved.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenic potential of ACTICLATE (doxycycline hyclate) and ACTICLATE CAP (doxycycline hyclate) have not been conducted.

However, a 2 year carcinogenicity study with doxycycline administered daily by oral gavage to adult rats (20, 75, 200 mg/kg/day) demonstrated an increase in uterine polyps in female rats at 200 mg/kg/day (10 times the maximum recommended daily adult dose of ACTICLATE and ACTICLATE CAP based on body surface area comparison) with no change in tumor incidence in male rats at the same dose. A 2-year carcinogenicity study with doxycycline administered daily by oral gavage to adult male (maximum dose 150 mg/kg/day) and female (maximum dose 300 mg/kg/day) mice showed no changes in tumor incidence, at approximately 4 and 7 times the maximum recommended daily adult dose of ACTICLATE and ACTICLATE CAP, based on a body surface area comparison, respectively.

Mutagenesis and fertility studies have not been conducted with ACTICLATE and ACTICLATE CAP. Mutagenesis studies with doxycycline demonstrated no potential to cause genetic toxicity in an in vitro point mutation study with mammalian cells or in an in vivo micronucleus assay in CD-1 mice. However, data from an in vitro mammalian chromosomal aberration assay conducted in CHO cells suggest that doxycycline is a weak clastogen. Oral administration of doxycycline to Sprague-Dawley rats showed adverse effects on fertility and reproduction including increased time for mating, reduced sperm motility, velocity and concentration as well as increased pre and post implantation loss. Reduced sperm velocity was seen at the lowest dosage tested, 50 mg/kg/day which is 2.5 times the maximum recommended daily adult dose of ACTICLATE and ACTICLATE CAP. Although doxycycline impairs the fertility of rats when administered at sufficient dosages, the effect of ACTICLATE and ACTICLATE CAP on human fertility is unknown.

13.2 Animal Toxicology and/or Pharmacology

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

Minocycline, tetracycline PO4, methacycline, doxycycline, tetracycline base, oxytetracycline HCl, and tetracycline HCl, were goitrogenic in rats fed a low iodine diet. This goitrogenic effect was accompanied by high radioactive iodine uptake. Administration of minocycline also produced a large goiter with high radioiodine uptake in rats fed a relatively high iodine diet.

Treatment of various animal species with this class of drugs has also resulted in the induction of thyroid hyperplasia in the following: in rats and dogs (minocycline); in chickens (chlortetracycline); and in rats and mice (oxytetracycline). Adrenal gland hyperplasia has been observed in goats and rats treated with oxytetracycline.

Results of animal studies indicate that tetracyclines cross the placenta and are found in fetal tissues.

Storage

Store at 20° to 25°C (68° to 77°F) excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from light and moisture. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

FDA-Approved Patient Labeling

Instructions for Use

ACTICLATE® (‘aktəˌklāt)

(doxycycline hyclate)

tablets

for oral use

Read this Instructions for Use before you start using ACTICLATE and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

Note:

• Your healthcare provider may need to change your dose of ACTICLATE during treatment as needed.
• ACTICLATE tablets can be taken whole or broken at scored lines.
• ACTICLATE tablets are marked with scored lines and may be broken at these scored lines to provide the following doses:

150 mg treatment (take the entire whole tablet)

100 mg treatment (take two-thirds of the tablet)

50 mg treatment (take one-third of the tablet)

How to break your ACTICLATE tablet:

• Hold the tablet between your thumb and index finger close to the scored line for your dose of ACTICLATE as shown above.
• Apply enough pressure to break the tablet at the scored line.
• Do not break the ACTICLATE tablet in any other way.

AQUA PHARMACEUTICALS

an Almirall company

Manufactured by Catalent Pharma Solutions, Winchester, KY 40391

For Aqua Pharmaceuticals, an Almirall Company Exton, PA 19341

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Revised: 10/2017

Rx only