Oracea

1 INDICATIONS AND USAGE ORACEA is a tetracycline-class drug indicated for the treatment of only inflammatory lesions (papules and pustules) of rosacea in adult patients. ( 1. 1) Limitations of Use This formulation of doxycycline has not been evaluated in the treatment or prevention of infections. Do not use ORACEA for treating bacterial infections, providing antibacterial prophylaxis, or reducing the numbers or eliminating microorganisms associated with any bacterial disease. ORACEA has not been evaluated for the treatment of the erythematous, telangiectatic, or ocular components of rosacea.

1.1Indication

ORACEA is indicated for the treatment of only inflammatory lesions (papules and pustules) of rosacea in adult patients. No meaningful effect was demonstrated for generalized erythema (redness) of rosacea.

1.2Limitations of Use This

formulation of doxycycline has not been evaluated in the treatment or prevention of infections. Do not use ORACEA for treating bacterial infections, providing antibacterial prophylaxis, or reducing the numbers or eliminating microorganisms associated with any bacterial disease. To reduce the development of drug-resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs, ORACEA should be used only as indicated.

ORACEA has not been evaluated for the treatment of the erythematous, telangiectatic, or ocular components of rosacea.

Take one ORACEA capsule (40 mg) once daily in the morning on an empty stomach, preferably at least one hour prior to or two hours after meals. Exceeding the recommended dosage may result in an increased incidence of side effects including the development of resistant microorganisms. ( 2.2 , 5.9 )

2.1General Dosing Information Take

one ORACEA capsule (40 mg) once daily in the morning on an empty stomach, preferably at least one hour prior to or two hours after meals. Administration of adequate amounts of fluid along with the capsules is recommended to wash down the capsule to reduce the risk of esophageal irritation and ulceration .

2.2Important Considerations for Dosing Regimen The

dosage of ORACEA differs from that of doxycycline used to treat infections. Exceeding the recommended dosage may result in an increased incidence of side effects including the development of resistant organisms.

The use of ORACEA during tooth development (the second and third trimesters of pregnancy, infancy and childhood up to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown) and reversible inhibition of bone growth. ( 5.1 , 5.2 , 8.1 , 8.4 ) Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of Clostridium difficile . If C. difficile associated diarrhea occurs, discontinue ORACEA. If renal impairment exists, ORACEA doses may need to be adjusted to avoid excessive systemic accumulations of the drug and possible liver injury. Photosensitivity can occur with ORACEA; Patients should minimize or avoid exposure to natural or artificial sunlight. Tetracyclines have been associated with the development of autoimmune syndromes; if symptoms develop, discontinue ORACEA immediately. ORACEA may cause pseudotumor cerebri (benign intracranial hypertension). Discontinue ORACEA if symptoms occur. Bacterial resistance to tetracyclines may develop in patients using ORACEA. It should only be used as indicated.

5.1Inhibition of Bone Growth During Fetal

and Pediatric Development Doxycycline, like other tetracycline-class drugs, may cause inhibition of bone growth when administered during the second and third trimesters of pregnancy, infancy, and childhood. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature human infants given oral tetracycline in doses of 25 mg/kg every 6 hours.

This reaction was shown to be reversible when the drug was discontinued. If doxycycline is used during the second or third trimester of pregnancy, advise the patient of the potential risk to the fetus .

5.2Tooth Discoloration During Fetal and Pediatric

Development The use of tetracycline class drugs orally during tooth development (last half of pregnancy, infancy, and childhood up 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 drug but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported.

Use of tetracycline drugs is not recommended during tooth development .

5.3Clostridium

difficile Associated Diarrhea (CDAD) Clostridium difficile associated diarrhea (CDAD) has been reported with nearly all antibacterial agents, including doxycycline, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use.

Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate management should be instituted as clinically indicated.

5.4Metabolic Effects The

anti-anabolic action of the tetracyclines may cause an increase in BUN. While this is not a problem in those with normal renal function, in patients with significantly impaired function, higher serum levels of tetracycline-class antibiotics may lead to azotemia, hyperphosphatemia, and acidosis. If renal impairment exists, even usual oral or parenteral doses may lead to excessive systemic accumulations of the drug and possible liver toxicity. Under such conditions, lower than usual total doses are indicated, and if therapy is prolonged, serum level determinations of the drug may be advisable.

5.5Photosensitivity Photosensitivity

manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Although this was not observed during the duration of the clinical studies with ORACEA, patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using ORACEA. If patients need to be outdoors while using ORACEA, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician.

5.6Autoimmune Syndromes Tetracyclines

have been associated with the development of autoimmune syndromes. Symptoms may be manifested by fever, rash, arthralgia, and malaise. In symptomatic patients, liver function tests, ANA, CBC, and other appropriate tests should be performed to evaluate the patients. Use of all tetracycline-class drugs should be discontinued immediately.

5.7Tissue Hyperpigmentation Tetracycline-class

drugs are known to cause hyperpigmentation. Tetracycline therapy may induce hyperpigmentation in many organs, including nails, bone, skin, eyes, thyroid, visceral tissue, oral cavity (teeth, mucosa, alveolar bone), sclerae and heart valves. Skin and oral pigmentation has been reported to occur independently of time or amount of drug administration, whereas other pigmentation has been reported to occur upon prolonged administration.

Skin pigmentation includes diffuse pigmentation as well as over sites of scars or injury.

5.8Pseudotumor Cerebri Pseudotumor

cerebri (benign intracranial hypertension) in adults has been associated with the use of tetracyclines. The usual clinical manifestations are headache and blurred vision. Bulging fontanels have been associated with the use of tetracyclines in infants. While both of these conditions and related symptoms usually resolve after discontinuation of the tetracycline, the possibility for permanent sequelae exists.

Patients should be questioned for visual disturbances prior to initiation of treatment with tetracyclines and should be routinely checked for papiledema while on treatment.

5.9Development of Drug Resistant Bacteria Bacterial

resistance to tetracyclines may develop in patients using ORACEA. Because of the potential for drug-resistant bacteria to develop during the use of ORACEA, it should only be used as indicated.

5.10Superinfection As with

other antibiotic preparations, use of ORACEA may result in overgrowth of non-susceptible microorganisms, including fungi. If superinfection occurs, ORACEA should be discontinued and appropriate therapy instituted. Although not observed in clinical trials with ORACEA, the use of tetracyclines may increase the incidence of vaginal candidiasis.

ORACEA should be used with caution in patients with a history of or predisposition to Candida overgrowth.

5.11Laboratory Monitoring Periodic

laboratory evaluations of organ systems, including hematopoietic, renal and hepatic studies should be performed. Appropriate tests for autoimmune syndromes should be performed as indicated.

5.12Fixed Drug Eruptions 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 reactions occur, discontinue ORACEA immediately and initiate appropriate therapy.

4 CONTRAINDICATIONS ​This drug is contraindicated in persons who have shown hypersensitivity to doxycycline or any of the other tetracyclines. ORACEA is contraindicated in persons who have shown hypersensitivity to doxycycline or other tetracyclines.

8.1Pregnancy Risk Summary Doxycycline

may cause reversible inhibition of bone growth and permanent discoloration of deciduous teeth when administered during the second and third trimesters of pregnancy . Available data from published studies have not shown a difference in major birth defect risk with doxycycline exposure in the first trimester of pregnancy compared to unexposed pregnancies. Avoid use of ORECEA during the second and third trimester of pregnancy. The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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. Data Human Data Published studies, including epidemiological and observational studies, with use of doxycycline during the first trimester of pregnancy have not identified drug-related increases in major birth defects.

The use of tetracycline during tooth development (second and third trimester of pregnancy) may cause permanent discoloration of deciduous teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drug but has been observed following repeated short- term courses. Animal Data Results from animal studies indicate that doxycycline crosses the placenta and is found in fetal tissues.

Some of the most common adverse reactions (incidence >2% and more common than with placebo) are nasopharyngitis, sinusitis, diarrhea, hypertension and aspartate aminotransferase increase. To report SUSPECTED ADVERSE REACTIONS, contact Galderma Laboratories, L.P. at 1-866-735-4137 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience Because

clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Clinical Trials of ORACEA: In controlled clinical trials of adult subjects with mild to moderate rosacea, 537 subjects received ORACEA or placebo over a 16-week period. The following table summarizes selected adverse reactions that occurred in the clinical trials at a rate of ≥1% for the active arm: Table 1.

Incidence (%) of Selected Adverse Reactions in Clinical Trials of ORACEA (n=269) v.s. Placebo (n=268) ORACEA Placebo Nasopharyngitis 13 9 Pharyngolaryngeal Pain 3 2 Sinusitis 7 2 Nasal Congestion 4 2 Fungal Infection 5 1 Influenza 5 3 Diarrhea 12 7 Abdominal Pain Upper 5 1 Abdominal Distention 3 1 Abdominal Pain 3 1 Stomach Discomfort 3 2 Dry Mouth 3 0 Hypertension 8 2 Blood Pressure Increase 4 1 Aspartate Aminotransferase Increase 6 2 Blood Lactate Dehydrogenase Increase 4 1 Blood Glucose Increase 3 0 Anxiety 4 0 Pain 4 1 Back Pain 3 0 Sinus Headache 3 0 Note: Percentages based on total number of study participants in each treatment group. Adverse Reactions for Tetracyclines: The following adverse reactions have been observed in patients receiving tetracyclines at higher, antimicrobial doses: Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with vaginal candidiasis) in the anogenital region.

Hepatotoxicity, Esophagitis and esophageal ulcerations have been reported in patients receiving the capsule forms of the drugs in the tetracycline-class. Most of the patients experiencing esophagitis and/or esophageal ulceration took their medication immediately before lying down . Renal toxicity: Rise in BUN has been reported and is apparently dose-related . Skin: maculopapular and erythematous rashes. Exfoliative dermatitis.

Photosensitivity is discussed above . Hypersensitivity reactions: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus. Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia.

6.2Postmarketing Adverse Reactions 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. The following adverse reactions have been identified during post approval use of ORACEA. Nervous system : Pseudotumor cerebri (benign intracranial hypertension), headache. Skin : fixed drug eruption Psychiatric : depression, anxiety, suicidal ideation, insomnia, abnormal dreams, hallucination