Professional Information — Claravis

Indications and Usage

Severe Recalcitrant Nodular Acne

Claravis (isotretinoin capsules) is indicated for the treatment of severe recalcitrant nodular acne. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. “Severe,” by definition,² means “many” as opposed to “few or several” nodules. Because of significant adverse effects associated with its use, Claravis should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, Claravis is indicated only for those patients who are not pregnant, because Claravis can cause life threatening birth defects (see Boxed CONTRAINDICATIONS AND WARNINGS ).

A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of disease in many patients.^1,3,4 If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience has shown that patients may continue to improve while off Claravis. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth (see WARNINGS, Skeletal, Bone Mineral Density,  Hyperostosis,  Premature Epiphyseal Closure ).

Dosage and Administration

Claravis should be administered with a meal (see PRECAUTIONS, Information for Patients ).

The recommended dosage range for Claravis is 0.5 to 1 mg/kg/day given in two divided doses with food for 15 to 20 weeks. In studies comparing 0.1, 0.5, and 1 mg/kg/day⁸, it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects – some of which may be dose related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2 mg/kg/day, as tolerated. Failure to take Claravis with food will significantly decrease absorption. Before upward dose adjustments are made, the patients should be questioned about their compliance with food instructions.

The safety of once daily dosing with Claravis has not been established. Once daily dosing is not recommended.

If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of Claravis, even in low doses, has not been studied, and is not recommended. It is important that Claravis be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Claravis on bone loss is unknown (see WARNINGS, Skeletal, Bone Mineral Density, Hyperostosis , and Premature Epiphyseal Closure ).

Contraceptive measures must be followed for any subsequent course of therapy (see PRECAUTIONS ).

*See DOSAGE AND ADMINISTRATION: the recommended dosage range is 0.5 to 1 mg/kg/day.

INFORMATION FOR PHARMACISTS

Access the iPLEDGE REMS system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) to obtain an authorization and the “do not dispense to patient after” date.  Claravis must only be dispensed in no more than a 30-day supply.

REFILLS REQUIRE A NEW PRESCRIPTION AND A NEW AUTHORIZATION FROM THE iPLEDGE SYSTEM.

A Claravis Medication Guide must be given to the patient each time Claravis is dispensed, as required by law. This Claravis Medication Guide is an important part of the risk management program for the patient.

Contraindications

Pregnancy: Category X. See Boxed CONTRAINDICATIONS AND WARNINGS.

Allergic Reactions

Claravis is contraindicated in patients who are hypersensitive to this medication or to any of its components (see PRECAUTIONS, Hypersensitivity ).

Adverse Reactions

Clinical Trials and Postmarketing Surveillance

The adverse reactions listed below reflect the experience from investigational studies of Claravis, and the postmarketing experience. The relationship of some of these events to Claravis therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving Claravis are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, e.g., of the lips, nasal passage, and eyes).

Dose Relationship

Cheilitis and hypertriglyceridemia are usually dose related. Most adverse reactions reported in clinical trials were reversible when therapy was discontinued; however, some persisted after cessation of therapy (see WARNINGS and ADVERSE REACTIONS ).

Body as a Whole
allergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS, Hypersensitivity ), edema, fatigue, lymphadenopathy, weight loss.

Cardiovascular
palpitation, tachycardia, vascular thrombotic disease, stroke.

Endocrine/Metabolic
hypertriglyceridemia (see WARNINGS, Lipids ), alterations in blood sugar levels (see PRECAUTIONS, Laboratory Tests ).

Gastrointestinal
inflammatory bowel disease (see WARNINGS, Inflammatory Bowel Disease ), hepatitis (see WARNINGS, Hepatotoxicity ), pancreatitis (see WARNINGS, Lipids ), bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms.

Hematologic
allergic reactions (see PRECAUTIONS, Hypersensitivity ), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see PRECAUTIONS, Information for Patients ). See PRECAUTIONS, Laboratory Tests for other hematological parameters.

Musculoskeletal
skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases in bone mineral density (see WARNINGS, Skeletal ), musculoskeletal symptoms (sometimes severe) including back pain, myalgia, and arthralgia (see PRECAUTIONS, Information for Patients ), transient pain in the chest (see PRECAUTIONS, Information for Patients ), arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see PRECAUTIONS, Laboratory Tests ).

Neurological
pseudotumor cerebri (see WARNINGS, Pseudotumor Cerebri ), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness.

Psychiatric
suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see WARNINGS, Psychiatric Disorders ), emotional instability.
Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.

Reproductive System
abnormal menses.

Respiratory
bronchospasms (with or without a history of asthma), respiratory infection, voice alteration.

Skin and Appendages
acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas,⁷ erythema multiforme, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including Wegener's granulomatosis; see PRECAUTIONS, Hypersensitivity ), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see PRECAUTIONS, Information for Patients ).

Special Senses

Hearing
hearing impairment (see WARNINGS, Hearing Impairment ), tinnitus.

Vision
corneal opacities (see WARNINGS, Corneal Opacities ), decreased night vision which may persist (see WARNINGS, Decreased Night Vision ), cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances.

Urinary System
glomerulonephritis (see PRECAUTIONS, Hypersensitivity ), nonspecific urogenital findings (see PRECAUTIONS, Laboratory Tests for other urological parameters).

Laboratory

Elevation of plasma triglycerides (see WARNINGS, Lipids ), decrease in serum high-density lipoprotein (HDL) levels, elevations of serum cholesterol during treatment.

Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see WARNINGS, Hepatotoxicity ).

Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS, Laboratory Tests ), hyperuricemia.

Decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis; see PRECAUTIONS, Information for Patients ), elevated sedimentation rates, elevated platelet counts, thrombocytopenia.

White cells in the urine, proteinuria, microscopic or gross hematuria.

Drug Interactions

• Vitamin A: Because of the relationship of Claravis to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects.
• Tetracyclines: Concomitant treatment with Claravis and tetracyclines should be avoided because Claravis use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines.
• Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) may be an inadequate method of contraception during Claravis therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from patients who can become pregnant who have used combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products. These reports are more frequent for patients who can become pregnant who use only a single form of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with Claravis. Therefore, it is critically important for patients who can become pregnant to select and commit to use two forms of effective contraception simultaneously, at least one of which must be a primary form (see PRECAUTIONS ).
• Norethindrone/ethinyl estradiol: In a study of 31 premenopausal female patients with severe recalcitrant nodular acne receiving Ortho-Novum^® 7/7/7 Tablets as an oral contraceptive agent, Claravis at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.
• St. John’s Wort: Claravis use is associated with depression in some patients (see WARNINGS,  Psychiatric Disorders and ADVERSE REACTIONS, Psychiatric). Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John’s Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John’s Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John’s Wort.
• Phenytoin: Claravis has not been shown to alter the pharmacokinetics of phenytoin in a study in seven healthy volunteers. These results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human hepatic P450 enzyme. Phenytoin is known to cause osteomalacia. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between phenytoin and Claravis. Therefore, caution should be exercised when using these drugs together.
• Systemic Corticosteroids: Systemic corticosteroids are known to cause osteoporosis. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and Claravis. Therefore, caution should be exercised when using these drugs together.

Overdosage

The oral LD₅₀ of isotretinoin is greater than 4000 mg/kg in rats and mice (>600 times the recommended clinical dose of 1 mg/kg/day after normalization of the rat dose for total body surface area and >300 times the recommended clinical dose of 1 mg/kg/day after normalization of the mouse dose for total body surface area) and is approximately 1960 mg/kg in rabbits (653 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area). In humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. These symptoms quickly resolve without apparent residual effects.

Claravis causes life threatening birth defects at any dosage (see Boxed CONTRAINDICATIONS AND WARNINGS ). Patients who can become pregnant who present with isotretinoin overdose must be evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to the fetus, as described in the Boxed CONTRAINDICATIONS AND WARNINGS . Non-pregnant patients must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as described in PRECAUTIONS . Educational materials for such patients can be obtained by calling the manufacturer. Because an overdose would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, male patients should use a condom, or avoid reproductive sexual activity with a patient who is or might become pregnant, for one month after the overdose. All patients with isotretinoin overdose should not donate blood for at least one month.

Description

Isotretinoin, USP a retinoid, is available as Claravis^™ (isotretinoin capsules USP), in 10 mg, 20 mg, 30 mg and 40 mg hard gelatin capsules for oral administration. Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow to orange crystalline powder. The structural formula is:

C₂₀H₂₈O₂                                       Molecular Weight: 300.44

Each capsule contains the following inactive ingredients: butylated hydroxyanisole, edetate disodium, gelatin, hydrogenated vegetable oil, polysorbate 80, soybean oil, titanium dioxide, white wax (beeswax), and vitamin E.

In addition, the 10 mg capsule contains black iron oxide and FD&C yellow no. 6. The 20 mg capsule contains black iron oxide, red iron oxide and yellow iron oxide. The 30 mg capsule contains red iron oxide and yellow iron oxide. The 40 mg capsule contains FD&C yellow no. 6.

The edible imprinting ink contains: 10 mg strength, D&C red no. 7 calcium lake, FD&C yellow no. 6 aluminum lake, propylene glycol, shellac glaze, and titanium dioxide; 20 mg strength, ammonium hydroxide, propylene glycol, shellac glaze, simethicone and titanium dioxide; 30 mg strength, D&C yellow no. 10 aluminum lake, FD&C blue no.1 aluminum lake, FD&C blue no. 2 aluminum lake, FD&C red no. 40 aluminum lake, iron oxide black, propylene glycol, and shellac glaze; 40 mg strength, ammonium hydroxide, iron oxide black, propylene glycol, and shellac glaze.

Meets dissolution test 2.

Clinical Pharmacology

Isotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1 mg/kg/day (see DOSAGE AND ADMINISTRATION ), inhibits sebaceous gland function and keratinization. The exact mechanism of action of isotretinoin is unknown.

Nodular Acne

Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of treatment with Claravis, and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.¹

Pharmacokinetics

Absorption

Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high-fat meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (2 x 40 mg capsules) of Claravis under fasted and fed conditions. Both peak plasma concentration (C_max) and the total exposure (AUC) of isotretinoin were more than doubled following a standardized high-fat meal when compared with Claravis given under fasted conditions (see Table 2). The observed elimination half-life was unchanged. This lack of change in half-life suggests that food increases the bioavailability of isotretinoin without altering its disposition. The time to peak concentration (T_max) was also increased with food and may be related to a longer absorption phase. Therefore, Claravis capsules should always be taken with food (see DOSAGE AND ADMINISTRATION ). Clinical studies have shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin.

Distribution

Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.

Metabolism

Following oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin.

After a single 80 mg oral dose of isotretinoin to 74 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions.

All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of isotretinoin to adult cystic acne patients (≥18 years), the exposure of patients to 4-oxo-isotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin.

In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces.

Elimination

Following oral administration of an 80 mg dose of ¹⁴C-isotretinoin as a liquid suspension, ¹⁴C-activity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a single 80 mg oral dose of isotretinoin to 74 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (t_½) of isotretinoin and 4-oxo-isotretinoin were 21 ± 8.2 hours and 24 ± 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.9 to 5.43 in patients with cystic acne.

Special Patient Populations

Pediatric Patients

The pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients (≥18 years) who received isotretinoin for the treatment of severe recalcitrant nodular acne. In both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed. The dose-normalized pharmacokinetic parameters for isotretinoin following single and multiple doses are summarized in Table 3 for pediatric patients. There were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and adult patients.

In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t_½) of isotretinoin and 4-oxo-isotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. The accumulation ratios of isotretinoin ranged from 0.46 to 3.65 for pediatric patients.

How Supplied / Storage and Handling

Claravis^™ (isotretinoin capsules USP) is available as:

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Protect from light.

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

Patient Counseling Information

See PRECAUTIONS and Boxed CONTRAINDICATIONS AND WARNINGS .

• Patients must be instructed to read the Medication Guide supplied as required by law when Claravis is dispensed. The complete text of the Medication Guide is reprinted at the end of this document. For additional information, patients must also be instructed to read the iPLEDGE REMS patient educational materials. All patients must sign the Patient Enrollment Form for Patients who cannot get Pregnant.
• Patients who can become pregnant must be instructed that they must not be pregnant when Claravis therapy is initiated, and that they should use two forms of effective contraception simultaneously for one month before starting Claravis, while taking Claravis, and for one month after Claravis has been stopped, unless they commit to continuous abstinence from not having any sexual contact with a partner that could result in pregnancy. They should also sign a second Patient Enrollment Form for Patients who can get Pregnant prior to beginning Claravis therapy. Patients who can become pregnant should be seen by their prescribers monthly and have a urine or serum pregnancy test, in a CLIA-certified laboratory, performed each month during treatment to confirm negative pregnancy status before another Claravis prescription is written (see Boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS ).
• Claravis is found in the semen of male patients taking Claravis, but the amount delivered to a patient who can become pregnant would be about one million times lower than an oral dose of 40 mg. While the no-effect limit for isotretinoin induced embryopathy is unknown, 20 years of postmarketing reports include four with isolated defects compatible with features of retinoid exposed fetuses; however two of these reports were incomplete, and two had other possible explanations for the defects observed.
• Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, prior to initiation of isotretinoin treatment, patients and family members should be asked about any history of psychiatric disorder, and at each visit during treatment patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. Signs and symptoms of depression include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses, and persistent physical symptoms unresponsive to treatment. Patients should stop isotretinoin and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of isotretinoin treatment may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient’s family. A referral to a mental health professional may be necessary. The physician should consider whether isotretinoin therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of isotretinoin therapy.
• Patients must be informed that some patients, while taking isotretinoin or soon after stopping isotretinoin, have become depressed or developed other serious mental problems. Symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating. Some patients taking isotretinoin have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. There were reports that some of these people did not appear depressed. There have been reports of patients on isotretinoin becoming aggressive or violent. No one knows if isotretinoin caused these behaviors or if they would have happened even if the person did not take isotretinoin. Some people have had other signs of depression while taking isotretinoin.
• Patients must be informed that they must not share Claravis with anyone else because of the risk of birth defects and other serious adverse events.
• Patients must be informed not to donate blood during therapy and for one month following discontinuation of the drug because the blood might be given to a pregnant patient whose fetus must not be exposed to Claravis.
• Patients should be reminded to take Claravis with a meal (see DOSAGE AND ADMINISTRATION ). To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid.
• Patients should be informed that transient exacerbation (flare) of acne has been seen, generally during the initial period of therapy.
• Wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided during Claravis therapy and for at least 6 months thereafter due to the possibility of scarring (see ADVERSE REACTIONS, Skin and Appendages).
• Patients should be advised to avoid prolonged exposure to UV rays or sunlight.
• Patients should be informed that they may experience decreased tolerance to contact lenses during and after therapy.
• Patients should be informed that approximately 16% of patients treated with Claravis in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of the drug. Transient pain in the chest has been reported less frequently. In the clinical trial, these symptoms generally cleared rapidly after discontinuation of Claravis, but in some cases persisted (see ADVERSE REACTIONS, Musculoskeletal). There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity (see Laboratory Tests, CPK).
• Pediatric patients and their caregivers should be informed that approximately 29% (104/358) of pediatric patients treated with Claravis developed back pain. Back pain was severe in 13.5% (14/104) of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of Claravis. Consideration should be given to discontinuation of Claravis if any significant abnormality is found.
• Neutropenia and rare cases of agranulocytosis have been reported. Claravis should be discontinued if clinically significant decreases in white cell counts occur.
• Patients should be advised that severe skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported in post-marketing data. Claravis should be discontinued if clinically significant skin reactions occur. 

Hypersensitivity

Anaphylactic reactions and other allergic reactions have been reported. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement (including renal) have been reported. Severe allergic reaction necessitates discontinuation of therapy and appropriate medical management.

Drug Interactions

• Vitamin A: Because of the relationship of Claravis to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects.
• Tetracyclines: Concomitant treatment with Claravis and tetracyclines should be avoided because Claravis use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines.
• Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) may be an inadequate method of contraception during Claravis therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from patients who can become pregnant who have used combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products. These reports are more frequent for patients who can become pregnant who use only a single form of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with Claravis. Therefore, it is critically important for patients who can become pregnant to select and commit to use two forms of effective contraception simultaneously, at least one of which must be a primary form (see PRECAUTIONS ).
• Norethindrone/ethinyl estradiol: In a study of 31 premenopausal female patients with severe recalcitrant nodular acne receiving Ortho-Novum^® 7/7/7 Tablets as an oral contraceptive agent, Claravis at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.
• St. John’s Wort: Claravis use is associated with depression in some patients (see WARNINGS,  Psychiatric Disorders and ADVERSE REACTIONS, Psychiatric). Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John’s Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John’s Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John’s Wort.
• Phenytoin: Claravis has not been shown to alter the pharmacokinetics of phenytoin in a study in seven healthy volunteers. These results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human hepatic P450 enzyme. Phenytoin is known to cause osteomalacia. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between phenytoin and Claravis. Therefore, caution should be exercised when using these drugs together.
• Systemic Corticosteroids: Systemic corticosteroids are known to cause osteoporosis. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and Claravis. Therefore, caution should be exercised when using these drugs together.