HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`
`ORACEA® safely and effectively. See full prescribing information for
`
`
`
`ORACEA.
`
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`ORACEA (doxycycline) capsules for oral use
`
`Initial U.S. Approval: 1967
`
`----------------------------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. (1.2)
`
`
`ORACEA has not been evaluated for the treatment of the erythematous,
`
`
`telangiectatic, or ocular components of rosacea. (1.2)
`
`
`
`
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`
`
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`
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`
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`•
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`If renal impairment exists, ORACEA doses may need to be adjusted to
`
`avoid excessive systemic accumulations of the drug and possible liver
`
`injury. (5.4)
`
`
`• Photosensitivity can occur with ORACEA; Patients should minimize or
`
`
`avoid exposure to natural or artificial sunlight. (5.5)
`
`• Tetracyclines have been associated with the development of autoimmune
`
`
`
`
`syndromes; if symptoms develop, discontinue ORACEA immediately.
`
`(5.6)
`
`
`• ORACEA may cause pseudotumor cerebri (benign intracranial
`
`
`hypertension). Discontinue ORACEA if symptoms occur. (5.8)
`
`
`
`• Bacterial resistance to tetracyclines may develop in patients using
`
`
`
`ORACEA. It should only be used as indicated. (5.9)
`
`
`
`
`------------------------------ADVERSE REACTIONS------------------------------­
`
`Some of the most common adverse reactions (incidence >2% and more
`
`common than with placebo) are nasopharyngitis, sinusitis, diarrhea,
`
`
`hypertension and aspartate aminotransferase increase. (6)
`
`
`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.
`
`
`------------------------------DRUG INTERACTIONS------------------------------­
`
`
`• Patients on anticoagulant therapy may require downward adjustment of
`
`
`their anticoagulant dosage. (7.1)
`
`
`
`• Some bacteriostatic drugs may interfere with the bactericidal action of
`penicillin, it is advisable to avoid giving tetracycline-class drugs in
`
`
`conjunction with penicillin. (7.2)
`
`• The concurrent use of tetracycline and methoxyflurane has been reported
`
`
`
`
`
`to result in fatal renal toxicity. (7.3)
`
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------­
`
`Lactation: Breastfeeding is not recommended (8.2)
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`
`See 17 for PATIENT COUNSELING INFORMATION and FDA­
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`
`approved patient labeling.
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`Revised: 12/2021
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`
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`----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`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. (2.1)
`
`
`Exceeding the recommended dosage may result in an increased incidence of
`
`
`side effects including the development of resistant microorganisms. (2.2, 5.9)
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`
`40 mg capsule. (3)
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`
`ORACEA is contraindicated in persons who have shown hypersensitivity to
`
`
`doxycycline or other tetracyclines. (4)
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`• 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. (5.3)
`______________________________________________________________________________________________________________________________________
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`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`INDICATIONS AND USAGE
`
`
`1.1 Indication
`
`
`1.2 Limitations of Use
`
`
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`2 DOSAGE AND ADMINISTRATION
`
`
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`2.1 General Dosing Information
`
`
`
`2.2 Important Considerations for Dosing Regimen
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`CONTRAINDICATIONS
`4
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`
`5.1 Inhibition of Bone Growth During Fetal and Pediatric Development
`
`
`
`
`
`
`5.2 Tooth Discoloration During Fetal and Pediatric Development
`
`
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`5.3 Clostridium difficile Associated Diarrhea
`
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`5.4 Metabolic Effects
`
`
`5.5 Photosensitivity
`
`
`5.6 Autoimmune Syndromes
`
`
`5.7 Tissue Hyperpigmentation
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`5.8 Pseudotumor Cerebri
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`5.9 Development of Drug Resistant Bacteria
`
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`5.10 Superinfection
`
`
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`5.11 Laboratory Monitoring
`
`ADVERSE REACTIONS
`
`
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`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing Experience
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`DRUG INTERACTIONS
`
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`7.1 Anticoagulants
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`6
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`7
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`8
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`8
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`7.2 Penicillin
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`7.3 Methoxyflurane
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`7.4 Antacids and Iron Preparations
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`
`7.5 Oral Retinoids
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`7.6 Barbiturates and Anti-epileptics
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`
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`7.7 Drug/Laboratory Test Interactions
`
`USE IN SPECIFIC POPULATIONS
`
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`8.1 Pregnancy
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`8.2 Lactation
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`8.4 Pediatric Use
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`8.5 Geriatric Use
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`10 OVERDOSAGE
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`11 DESCRIPTION
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`12 CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
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`12.3 Pharmacokinetics
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`12.4 Microbiology
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`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`14 CLINICAL STUDIES
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`16 HOW SUPPLIED/STORAGE AND HANDLING
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`17 PATIENT COUNSELING INFORMATION
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`*Sections or subsections omitted from the full prescribing information are not
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`listed.
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`_______________________________________________________________________________________________________________________________________
`
`Reference ID: 4902752
`
`

`

`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`1
`INDICATIONS AND USAGE
`
`
`
`
`1.1 Indication
`
`
`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.
`
`
`
`1.2 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.
`
`
`
`
`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.
`
`
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`
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`
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`ORACEA has not been evaluated for the treatment of the erythematous, telangiectatic, or ocular components of rosacea.
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 General 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.
`
`
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`
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`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
`
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`[see Adverse Reactions (6)].
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`2.2 Important Considerations for Dosing Regimen
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`
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`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.
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`
`
`3 DOSAGE FORMS AND STRENGTHS
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`40 mg beige opaque capsule imprinted with “GLD 40”
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`4 CONTRAINDICATIONS
`
`
`This drug is contraindicated in persons who have shown hypersensitivity to doxycycline or any other tetracyclines.
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`5 WARNINGS AND PRECAUTIONS
`
`
`
`5. 1 Inhibition of Bone Growth During Fetal and Pediatric Development
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`Doxycycline, like other tetracycline-class drugs, may cause inhibition of bone growth when administered during the second and third trimesters of pregnancy, infancy,
`
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`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
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`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
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`during the second or third trimester of pregnancy, advise the patient of the potential risk to the fetus [see Use in Specific Populations (8.1)].
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`5.2 Tooth Discoloration During Fetal and Pediatric Development
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`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
`
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`
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`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-
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`term courses. Enamel hypoplasia has also been reported. Use of tetracycline drugs is not recommended during tooth development [see Use in Specific Populations
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`(8.1)].
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`5.3 Clostridium difficile Associated Diarrhea (CDAD)
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`Clostridium difficile associated diarrhea (CDAD) has been reported with nearly all antibacterial agents, including doxycycline, and may range in severity from mild
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`diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
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`C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and
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`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
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`following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
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`If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate management should be instituted
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`as clinically indicated.
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`5.4 Metabolic Effects
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`
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`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
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`significantly impaired function, higher serum levels of tetracycline-class antibiotics may lead to azotemia, hyperphosphatemia, and acidosis. If renal impairment exists,
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`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
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`doses are indicated, and if therapy is prolonged, serum level determinations of the drug may be advisable.
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`5.5 Photosensitivity
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`Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Although this was not observed during the
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`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
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`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.
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`5.6 Autoimmune Syndromes
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`Tetracyclines have been associated with the development of autoimmune syndromes. Symptoms may be manifested by fever, rash, arthralgia, and malaise. In
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`symptomatic patients, liver function tests, ANA, CBC, and other appropriate tests should be performed to evaluate the patients. Use of all tetracycline-class drugs
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`should be discontinued immediately.
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`5.7 Tissue Hyperpigmentation
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`Tetracycline-class drugs are known to cause hyperpigmentation. Tetracycline therapy may induce hyperpigmentation in many organs, including nails, bone, skin, eyes,
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`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
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`Reference ID: 4902752
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`

`

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`or amount of drug administration, whereas other pigmentation has been reported to occur upon prolonged administration. Skin pigmentation includes diffuse
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`pigmentation as well as over sites of scars or injury.
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`5.8 Pseudotumor Cerebri
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`Pseudotumor cerebri (benign intracranial hypertension) in adults has been associated with the use of tetracyclines. The usual clinical manifestations are headache and
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`blurred vision. Bulging fontanels have been associated with the use of tetracyclines in infants. While both of these conditions and related symptoms usually resolve
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`after discontinuation of the tetracycline, the possibility for permanent sequelae exists. Patients should be questioned for visual disturbances prior to initiation of
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`treatment with tetracyclines and should be routinely checked for papiledema while on treatment.
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`5.9 Development of Drug Resistant Bacteria
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`
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`Bacterial resistance to tetracyclines may develop in patients using ORACEA. Because of the potential for drug-resistant bacteria to develop during the use of
`
`
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`ORACEA, it should only be used as indicated.
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`5.10 Superinfection
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`As with other antibiotic preparations, use of ORACEA may result in overgrowth of non-susceptible microorganisms, including fungi. If superinfection occurs,
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`ORACEA should be discontinued and appropriate therapy instituted. Although not observed in clinical trials with ORACEA, the use of tetracyclines may increase the
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`incidence of vaginal candidiasis. ORACEA should be used with caution in patients with a history of or predisposition to Candida overgrowth.
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`5.11 Laboratory Monitoring
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`Periodic laboratory evaluations of organ systems, including hematopoietic, renal and hepatic studies should be performed. Appropriate tests for autoimmune syndromes
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`should be performed as indicated.
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`6
`ADVERSE REACTIONS
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`6.1 Clinical Trials Experience
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`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
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`in the clinical trials of another drug and may not reflect the rates observed in practice.
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`Adverse Reactions in Clinical Trials of ORACEA: In controlled clinical trials of adult subjects with mild to moderate rosacea, 537 subjects received ORACEA or
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`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:
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` Table 1. Incidence (%) of Selected Adverse Reactions in Clinical
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` Trials of ORACEA (n=269) vs. Placebo (n=268)
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` ORACEA
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` Placebo
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` Nasopharyngitis
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` Pharyngolaryngeal Pain
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`
` Sinusitis
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` Nasal Congestion
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` Fungal Infection
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` Influenza
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` Diarrhea
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` Abdominal Pain Upper
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` Abdominal Distention
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` 13 (5)
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` 3 (1)
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` 7 (3)
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`
` 4 (2)
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` 5 (2)
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`
` 5 (2)
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`
` 12 (5)
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` 5 (2)
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`
` 3 (1)
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`
`
` 9 (3)
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`
`
` 2 (1)
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`
`
` 2 (1)
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`
`
` 2 (1)
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`
`
` 1 (0)
`
`
`
` 3 (1)
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`
`
` 7 (3)
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` 1 (0)
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`
`
` 1 (0)
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` 1 (0)
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` Abdominal Pain
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` Stomach Discomfort
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` Dry Mouth
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` Hypertension
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` 3 (1)
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` 3 (1)
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` 3 (1)
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` 8 (3)
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` Blood Pressure Increase
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` 4 (2)
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`Aspartate Aminotransferase
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` Increase
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`Blood Lactate
` Dehydrogenase Increase
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` Blood Glucose Increase
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` Anxiety
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` Pain
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`Reference ID: 4902752
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` 6 (2)
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` 4 (2)
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` 3 (1)
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` 4 (2)
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` 4 (2)
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` 2 (1)
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` 0 (0)
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` 2 (1)
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` 1 (0)
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` 2 (1)
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` 1 (0)
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` 0 (0)
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` 0 (0)
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` 1 (0)
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`

`

`
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` Back Pain
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` Sinus Headache
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` 3 (1)
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` 3 (1)
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` 0 (0)
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` 0 (0)
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`Note: Percentages based on total number of study participants in each treatment group.
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`Adverse Reactions for Tetracyclines: The following adverse reactions have been observed in patients receiving tetracyclines at higher, antimicrobial doses:
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`Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with vaginal candidiasis) in the anogenital region.
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`Hepatotoxicity. Esophagitis and esophageal ulcerations have been reported in patients receiving the capsule forms of the drugs in the tetracycline-class. Most of the
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`patients experiencing esophagitis and/or esophageal ulceration took their medication immediately before lying down [see Dosage and Administration (2)].
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`Renal toxicity: Rise in BUN has been reported and is apparently dose-related [see Warnings and Precautions (5.4)].
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`Skin: maculopapular and erythematous rashes. Exfoliative dermatitis . Photosensitivity is discussed above [see Warnings and Precautions (5.5)].
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`Hypersensitivity reactions: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus
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`
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`erythematosus.
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`Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia.
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`6.2 Postmarketing Experience
`
`
`
`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
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`relationship to drug exposure. The following adverse reactions have been identified during post approval use of ORACEA.Nervous system: Pseudotumor cerebri
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`(benign intracranial hypertension), headache.
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`7 DRUG INTERACTIONS
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`
`
`7.1 Anticoagulants
`
`
`
`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 tetracycline-class drugs in conjunction with penicillin.
`
`
`
`
`
`
`7.3 Methoxyflurane
`
`
`The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity.
`
`
`
`
`
`
`
`7.4 Antacids and Iron Preparations
`
`
`
`Absorption of tetracyclines is impaired by bismuth subsalicylate, proton pump inhibitors, antacids containing aluminum, calcium or magnesium and iron-containing
`
`
`
`
`preparations.
`
`
`7.5 Oral Retinoids
`
`
`
`There have been reports of pseudotumor cerebri (benign intracranial hypertension) associated with the concomitant use of isotretinoin and tetracyclines. Since both oral
`
`
`
`
`retinoids, including isotretinoin and acitretin, and the tetracyclines, primarily minocycline, can cause increased intracranial pressure, the concurrent use of an oral
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`
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`retinoid and a tetracycline should be avoided.
`
`
`7.6 Barbiturates and Anti-epileptics
`
`
`
`Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline.
`
`
`
`
`7.7 Drug/Laboratory Test Interactions
`
`
`
`False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`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 [see Warnings and Precautions (5.1 and 5.2)]. 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.
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`
`
`
`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
`
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`
`
`
`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.
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`
`
`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.
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`The use of tetracycline during tooth development (second and third trimester of pregnancy) may cause permanent discoloration of deciduous teeth (yellow-gray-brown).
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`
`
`This adverse reaction is more common during long-term use of the drug but has been observed following repeated short- term courses.
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`
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`
`
`Animal Data
`
`Results from animal studies indicate that doxycycline crosses the placenta and is found in fetal tissues.
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`
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`
`
`Reference ID: 4902752
`
`

`

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`
`
`
`
` 8.2 Lactation
`Risk Summary
`
`Based on available published data, doxycycline is likely to be present in human breast milk but the specific concentration in breastmilk is not clear. There is no
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`
`
`
`
`information on the effects of doxycycline on the breastfed infant or the effects on milk production. Because there are other antibacterial drug options available to treat
`
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`
`
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`rosacea in lactating women and because of the potential for serious adverse reactions, including tooth discoloration and inhibition of bone growth, advise patients that
`
`
`
`breastfeeding is not recommended during treatment with ORACEA and for 5 days after the last dose.
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`
`
`8.4 Pediatric Use
`
`
`
`ORACEA should not be used in infants and children less than 8 years of age [see Warnings and Precautions (5.1)]. ORACEA has not been studied in children of any
`
`
`
`
`age with regard to safety or efficacy, therefore use in children is not recommended.
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`
`
`8.5 Geriatric Use
`
`
`
`Clinical studies of ORACEA 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 elderly and younger patients. In general, dose selection for an elderly patient
`
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`
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`should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant
`
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`disease or other drug therapy.
`
`
`
`11 DESCRIPTION
`
`
`ORACEA (doxycycline, USP) Capsules 40 mg are hard gelatin capsule shells filled with two types of doxycycline beads (30 mg immediate release and 10 mg delayed
`
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`
`
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`release) that together provide a dose of 40 mg of anhydrous doxycycline (C22H24N2O8).
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`The structural formula of doxycycline, USP is:
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`
`with an empirical formula of C22H24N2O8•H2O and a molecular weight of 462.46. The chemical designation for doxycycline is 2-Naphthacenecar-boxamide,4­
`
`
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`(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-, [4S-(4α, 4aα, 5α, 5aα, 6α,12aα)]-, monohydrate. It is very slightly
`
`
`soluble in water.
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`Inert ingredients in the formulation are: hypromellose, iron oxide red, iron oxide yellow, methacrylic acid copolymer, polyethylene glycol, Polysorbate 80, sugar
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`spheres, talc, titanium dioxide, and triethyl citrate.
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`12 CLINICAL PHARMACOLOGY
`
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`12.1 Mechanism of Action
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`The mechanism of action of ORACEA in the treatment of inflammatory lesions of rosacea is unknown.
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`12.3 Pharmacokinetics
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`ORACEA capsules are not bioequivalent to other doxycycline products. The pharmacokinetics of doxycycline following oral administration of ORACEA was
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`investigated in 2 volunteer studies involving 61 adults. Pharmacokinetic parameters for ORACEA following single oral doses and at steady-state in healthy subjects are
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`presented in Table 2.
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` Table 2. Pharmacokinetic Parameters [Mean (±SD)] for ORACEA
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`Single Dose 40
`
` mg capsules
`
` Steady-State#
`
` 40 mg capsules
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`
`
` N
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` 30
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`
`
` 31
`
`Cmax*
`
` (ng/mL)
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`
` Tmax+ (hr)
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` 510 ± 220.7
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` 600 ± 194.2
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` 3.00
`
` (1.0-4.1)
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` 2.00
`
` (1.0-4.0)
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`
`AUC0-oo *
` (ng•hr/mL)
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`
`
` 9227±
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` 3212.8
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` 7543 ±
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` 2443.9
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` t1/2* (hr)
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` 21.2 ± 7.6
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` 23.2 ± 6.2
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`*Mean +Median
`#Day 7
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`Absorption: In a single-dose food-effect study involving administration of ORACEA to healthy volunteers, concomitant administration with a 1000 calorie,
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`high-fat, high-protein meal that included dairy products, resulted in a decrease in the rate and extent of absorption (Cmax and AUC) by about 45% and 22%,
`
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`respectively, compared to dosing under fasted conditions. This decrease in systemic exposure can be clinically significant, and therefore if ORACEA is
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`taken close to meal times, it is recommended that it be taken at least one hour prior to or two hours after meals.
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`Distribution: Doxycycline is greater than 90% bound to plasma proteins.
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`Metabolism: Major metabolites of doxycycline have not been identified. However, enzyme inducers such as barbiturates, carbamazepine, and phenytoin
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`decrease the half-life of doxycycline.
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`Excretion: Doxycycline is excreted in the urine and feces as unchanged drug. It is reported that between 29% and 55.4% of an administered dose can be
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`accounted for in the urine by 72 hours. Terminal half-life averaged 21.2 hours in subjects receiving a single dose of ORACEA.
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`Special Populations
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`Geriatric: Doxycycline pharmacokinetics have not been evaluated in geriatric patients.
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`Pediatric: Doxycycline pharmacokinetics have not been evaluated in pediatric patients [see Warnings and Precautions (5.1)].
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`Reference ID: 4902752
`
`

`

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` Gender: The pharmacokinetics of ORACEA were compared in 16 male and 14 female subjects under fed and fasted conditions. While female subjects had a
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` higher Cmax and AUC than male subjects, these differences were thought to be due to differences in body weight/lean body mass.
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`Race: Differences in doxycycline pharmacokinetics among racial groups have not been evaluated.
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`Renal Insufficiency: Studies have shown no significant difference in serum half-life of doxycycline in patients with normal and severely impaired renal
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`function. Hemodialysis does not alter the serum half-life of doxycycline.
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`Hepatic Insufficiency: Doxycycline pharmacokinetics have not been evaluated in patients with hepatic insufficiency.
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`Gastric Insufficiency: In a study in healthy volunteers (N=24) the bioavailability of doxycycline is reported to be reduced at high pH. This reduced
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`bioavailability may be clinically significant in patients with gastrectomy, gastric bypass surgery or who are otherwise deemed achlorhydric.
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`Drug Interactions: [see Drug Interactions (7)].
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`12.4 Microbiology
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`Doxycycline is a member of the tetracycline-class of drugs. The plasma concentrations of doxycycline achieved with ORACEA during administration [see Clinical
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`Pharmacology (12.3) and Dosage and Administration (2.2)] are less than the concentration required to treat bacterial diseases. ORACEA should not be used for treating
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`bacterial infections, providing antibacterial prophylaxis, or reducing the numbers or eliminating microorganisms associated with any bacterial disease [see Indications
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`and Usage (1.2)]. In vivo microbiological studies utilizing a similar drug exposure for up to 18 months demonstrated no detectable long term effects on bacterial flora
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`of the oral cavity, skin, intestinal tract and vagina.
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`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`Doxycycline was assessed for potential to induce carcinogenesis in a study in which the compound was administered to Sprague-Dawley rats by gavage at dosages of
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`20, 75, and 200 mg/kg/day for two years. An increased incidence of uterine polyps was observed in female rats that received 200 mg/kg/day, a dosage that resulted in a
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`systemic exposure to doxycycline approximately 12.2 times that observed in female humans who use ORACEA [exposure comparison based upon area under the curve
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`(AUC) values]. No impact upon tumor incidence was observed in male rats up to at 200 mg/kg/day, or in females at the lower dosages studied.
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`Doxycyline was assessed for potential to induce carcinogenesis in CD-1 mice by gavage at dosages 20, 75, and 150 mg/kg/day in males and at dosages of 20, 100, and
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`300 mg/kg/day in females. No impact upon tumor incidence was observed in male and female mice at systemic exposures approximately 4.2 and 8.3 times that
`
`observed in humans, respectively.
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`Doxycycline demonstrated no potential to cause genetic toxicity in an in vitro point mutation study with mammalian cells (CHO/HGPRT forward mutation assay) or in
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`an in vivo micronucleus assay conducted in CD-1 mice. However, data from an in vitro mammalian chromosomal aberration assay conducted with CHO cells suggest
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`that doxycycline is a weak clastogen. Oral administration of doxycycline to male and female Sprague-Dawley rats adversely affected fertility and reproductive
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`performance, as evidenced by increased time for mating to occur, reduced sperm motility, velocity, and concentration, abnormal sperm morphology, and increased pre­
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`and post-implantation losses. Doxycycline induced reproductive toxicity at all dosages that were examined in this study, as even the lowest dosage tested (50
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`mg/kg/day) induced a statistically significant reduction in sperm velocity. Note that 50 mg/kg/day is approximately 3.6 times the amount of doxycycline contained in
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`the recommended daily dose of ORACEA when compared on the basis of AUC estimates. Although doxycycline impairs the fertility of rats when administered at
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`sufficient dosage, the effect of ORACEA on human fertility is unknown.
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`14 CLINICAL STUDIES
`
`
`The safety and efficacy of ORACEA in the treatment of only inflammatory lesions (papules and pustules) of rosacea was evaluated in two randomized, placebo-
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`controlled, multi-centered, double-blind, 16-week Phase 3 trials involving 537 subjects (total of 269 subjects on ORACEA from the two trials) with rosacea (10 to 40
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`papules and pustules and two or fewer nodules). Mean baseline lesion counts were 20 and 21 for ORACEA and placebo subject groups respectively. Pregnant and
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`nursing women, subjects <18 years of age, and subjects with ocular rosacea and/or blepharitis/meibomianitis who require ophthalmologic treatment were excluded from
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`trials.
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`At Week 16, subjects in the ORACEA group were evaluated using co-primary endpoints of mean reduction in lesion counts and a dichotomized static Investigator’s
`
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`Global Assessment of Clear or Almost Clear (defined as 1 to 2 small papules or pustules) when compared to the placebo group in both Phase 3 trials.
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`Table 3: Clinical Results of ORACEA versus Placebo
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` Mean Change in Lesion Count
`
` from Baseline
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`
`
` Study 1
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` Study 2
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`
` ORACEA
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`
`
` Placebo
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`
`
` ORACEA
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`
`
` Placebo
`
`
` 40 mg
`
` N=127
`
`
`
` -11.8
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`
` N=124
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` -5.9
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` 40 mg
`
` N=142
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` -9.5
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`
` N=144
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`
`
` -4.3
`
` No. (%) of Subjects Clear or
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`
`
` Almost Clear in the IGA*
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`
` 39 (30.7%)
`
`24
` (19.4%)
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`
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`21
` (14.8%)
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`
` 9 (6.3%)
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`
`
` *Investigator’s Global Assessm