Absorica

Isotretinoin is used to treat severe, disfiguring nodular acne. It should be used only after other acne medicines have been tried and have failed to help the acne. Isotretinoin may also be used to treat other skin diseases as determined by your doctor.

Isotretinoin must not be used to treat women who are able to bear children unless other forms of treatment have been tried first and have failed. Isotretinoin must not be taken during pregnancy because it causes birth defects in humans. If you are able to bear children, it is very important that you read, understand, and follow the pregnancy warnings for isotretinoin.

This medicine is available only under a registered distribution program called the iPLEDGE™ program.

It is very important that your doctor check the progress of you or your child at regular visits to make sure this medicine is working properly. Blood tests may be needed to check for unwanted effects.

Isotretinoin causes birth defects in humans if taken during pregnancy. If you suspect that you may have become pregnant, stop taking this medicine and check with your doctor right away.

Using this medicine while you are pregnant can cause very serious birth defects. Use two forms of effective birth control to keep from getting pregnant one month before beginning treatment, while you are using this medicine (even if the medicine is temporarily stopped), and for at least 1 month after you stop taking the medicine. The most effective forms of birth control are hormone birth control pills, patches, shots, vaginal rings, or implants, an IUD, or a vasectomy (for men). One of these forms of birth control should be combined with a condom, a diaphragm, or a cervical cap.

Isotretinoin must not be taken by women of reproductive age unless two effective forms of birth control have been used for at least 1 month before the start of treatment. Contraception must be continued during the period of treatment, which is up to 20 weeks, and for 1 month after isotretinoin is stopped. Be sure you have discussed this information with your doctor.

If you are a woman who is able to have children, you must have 2 pregnancy tests before beginning treatment with isotretinoin to make sure you are not pregnant. The second pregnancy test must be taken at least 19 days after the first test and during the first 5 days of the menstrual period immediately prior to beginning treatment. In addition, you must have a pregnancy test each month while you are taking this medicine and 1 month after treatment is completed.

Do not take vitamin A or any vitamin supplement containing vitamin A while taking this medicine, unless otherwise directed by your doctor. To do so may increase the chance of side effects.

Do not take other medicines without checking first with your doctor. This includes vitamins, herbal products, and prescription or nonprescription (over-the-counter [OTC]) medicines. Some medicines or nutritional supplements (eg, St. John's wort) may cause your birth control pills to not work as well.

During the first 3 weeks you are taking isotretinoin, your skin may become irritated. Also, your acne may seem to get worse before it gets better. Check with your doctor if your skin condition does not improve within 1 to 2 months after starting this medicine or at any time your skin irritation becomes severe. Full improvement continues after you stop taking isotretinoin and may take up to 6 months. Your doctor can help you choose the right skin products to reduce skin dryness and irritation.

You or your child should not donate blood to a blood bank while using isotretinoin or for 30 days after you stop taking it. This is to prevent a pregnant patient from receiving blood that contains the medicine.

In some patients, isotretinoin may cause a decrease in night vision. This problem may occur suddenly. If it does occur, do not drive, use machines, or do anything else that could be dangerous if you are not able to see well. Also, check with your doctor.

Isotretinoin may cause dryness of the eyes. If you or your child wear contact lenses, your eyes may be more sensitive to them during the time you are taking isotretinoin and for up to 2 weeks after you stop taking it. To help relieve dryness of the eyes, check with your doctor about using a lubricating solution, such as artificial tears. If eye inflammation occurs, check with your doctor right away.

Isotretinoin may cause dryness of the mouth and nose. For temporary relief of mouth dryness, use sugarless candy or gum, melt bits of ice in your mouth, or use a saliva substitute. However, if dry mouth continues for more than 2 weeks, check with your medical doctor or dentist. Continuing dryness of the mouth may increase the chance of dental disease, including tooth decay, gum disease, and fungus infections.

Avoid overexposing your skin to sunlight, wind, or cold weather. Your skin will be more prone to sunburn, dryness, or irritation, especially during the first 2 or 3 weeks of treatment. However, you or your child should not stop taking this medicine unless the skin irritation becomes too severe. Do not use a sunlamp or tanning beds.

To help isotretinoin work properly, use sunscreen or sunblock lotions with a sun protection factor (SPF) of at least 15 on a regular basis. Also, wear protective clothing and hats.

Isotretinoin may cause some people to be agitated, irritable, or display other abnormal behaviors. It may also cause some people to have suicidal thoughts and tendencies or to become more depressed. If you, your child, or your caregiver notice any of these side effects, check with you doctor right away.

This medicine may increase pressure in your head. This may increase your risk of vision loss or serious brain problems. Check with your doctor right away if you have a bad headache, blurred vision, dizziness, nausea or vomiting, or seizures.

Serious skin reactions can occur with this medicine. Check with your doctor right away if you or your child have any of the following symptoms while using this medicine: blistering, peeling, or loosening of the skin, chills, diarrhea, itching, joint or muscle pain, rash, red skin lesions, often with a purple center, sores, ulcers, or white spots in the mouth or on the lips, or unusual tiredness or weakness.

Isotretinoin may cause bone or muscle problems, including joint pain, muscle pain or stiffness, or difficulty moving. You may get hurt more easily during rough sports. You may heal more slowly. If this medicine is for your child, tell the doctor if you think your child is not growing properly.

It is very important that you or your child not use wax epilation to remove hair while you are taking isotretinoin and for 6 months after stopping it. Isotretinoin can increase your chance of scarring from wax epilation.

It is very important that you or your child not have any cosmetic procedures to smooth your skin (eg, dermabrasion, laser) while you are taking isotretinoin and for 6 months after stopping it. Isotretinoin can increase your chance of scarring from these procedures.

This medicine may affect blood sugar levels. If you or your child are diabetic and notice a change in the results of your blood or urine sugar tests, check with your doctor.

Pancreatitis may occur while you are using this medicine. Tell your doctor right away if you or your child have sudden and severe stomach pain, chills, constipation, nausea, vomiting, fever, or lightheadedness.

Isotretinoin may cause some people to have hearing problems within a few weeks after they start taking it. Check with your doctor right away if you or your child have hearing loss, a continuing ringing or buzzing, or any other unexplained noise in the ears.

Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, unusual tiredness or weakness, or yellow eyes or skin. These could be symptoms of a serious liver problem.

Tell your doctor right away if you or your child have abdominal or stomach pain, rectal bleeding, or severe diarrhea. These may be symptoms of a serious condition called inflammatory bowel disease.

This medicine may cause serious allergic reactions, including anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Call your doctor right away if you have a rash, itching, redness, soreness, or itching skin, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth while you are using this medicine.

This medicine contains FD&C Yellow No.5 (tartrazine) which may cause an allergic reaction, including asthma, in some people. This reaction is more often seen in people who also have an allergy to aspirin.

This medicine lowers the number of some types of blood cells in your body. Because of this, you or your child may bleed or get infections more easily. To help with these problems, avoid being near people who are sick or have infections. Wash your hands often. Stay away from rough sports or other situations where you could be bruised, cut, or injured. Brush and floss your teeth gently. Be careful when using sharp objects, including razors and fingernail clippers.

Absorica is a retinoid indicated for the treatment of severe recalcitrant nodular acne in patients 12 years of age and older. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. “Severe,” by definition, means “many” as opposed to “few or several” nodules. Because of significant adverse reactions associated with its use, Absorica should be reserved for patients with multiple severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, Absorica is indicated only for those female patients who are not pregnant, because Absorica can cause severe birth defects [seeContraindications (4.1)].

Limitations of Use

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. 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 with isotretinoin has shown that patients may continue to improve following treatment with isotretinoin. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth [see Warnings and Precautions (5.12)].

As a part of the iPLEDGE program, Absorica may only be administered to patients enrolled in the program [see Warnings and Precautions (5.2)].

Pregnancy

Pregnancy Category X [see Contraindications (4) and Warnings and Precautions (5.1)].

Risk Summary

Absorica is contraindicated during pregnancy because isotretinoin can cause can cause fetal harm when administered to a pregnant woman. There is an increased risk of major congenital malformations, spontaneous abortions, and premature births following isotretinoin exposure during pregnancy in humans. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to a fetus.

Clinical Considerations

If pregnancy does occur during treatment of a female patient who is taking Absorica, Absorica must be discontinued immediately and she should be referred to an obstetrician-gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Human Data

Major congenital malformations that have been documented following isotretinoin exposure include malformations of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. External malformations include: skull; ear (including anotia, micropinna, small or absent external auditory canals); eye (including microphthalmia); facial dysmorphia and cleft palate. Internal abnormalities include: CNS (including cerebral and cerebellar malformations, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular; thymus gland; parathyroid hormone deficiency. In some cases death has occurred as a result of the malformations.

Isotretinoin is found in the semen of male patients taking isotretinoin, but the amount delivered to a female partner 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 and 20 years of post-marketing reports include four reports with isolated defects compatible with features of retinoid exposed fetuses, two of these reports were incomplete and two had other possible explanations for the defects observed.

Cases of IQ scores less than 85 with or without other abnormalities have been reported. An increased risk of spontaneous abortion and premature births have been documented with isotretinoin exposure during pregnancy.

Nursing Mothers

It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from Absorica, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The use of Absorica in pediatric patients less than 12 years of age has not been studied. The use of Absorica for the treatment of severe recalcitrant nodular acne in pediatric patients ages 12 to 17 years should be given careful consideration, especially for those patients where a known metabolic or structural bone disease exists [see Warnings and Precautions (5.12)]. Use of Absorica in this age group for severe recalcitrant nodular acne is supported by evidence from a clinical trial of Absorica compared to a generic product of Accutane® (isotretinoin) in 397 pediatric patients (12 to 17 years). Results from this trial demonstrated that both Absorica and the other isotretinoin drug product, at a dose of 1 mg/kg/day given in two divided doses, was effective in treating severe recalcitrant nodular acne in pediatric patients.

In trials with isotretinoin, adverse reactions reported in pediatric patients were similar to those described in adults except for the increased incidence of back pain and arthralgia (both of which were sometimes severe) and myalgia in pediatric patients. In a trial of pediatric patients treated with isotretinoin, approximately 29% (104/358) 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 Absorica. Consideration should be given to discontinuation of Absorica if any significant abnormality is found.

The effect on bone mineral density (BMD) of a 20-week course of therapy with Absorica or a generic product of Accutane® (isotretinoin) was evaluated in a double-blind, randomized clinical trial involving 396 adolescents with severe recalcitrant nodular acne (mean age 15.4, range 12-17, 80% males). Following 20 weeks of treatment, there were no statistically significant differences between the treatment groups. The mean changes in BMD from baseline for the overall trial population were 1.8% for lumbar spine, -0.1% for total hip and -0.3% for femoral neck. Mean BMD Z-scores declined from baseline at each of these sites (-0.053, -0.109 and -0.104 respectively). Out of 306 adolescents, 27 (8.8%) had clinically significant BMD declines defined as ≥4% lumbar spine or total hip, or ≥5% femoral neck, including 2 subjects for lumbar spine, 17 for total hip and 20 for femoral neck. Repeat DXA scans within 2-3 months after the post treatment scan showed no recovery of BMD. Longer-term follow up at 4-11 months showed that 3 out of 7 patients had total hip and femoral neck BMD below pre-treatment baseline, and 2 others did not show the increase in BMD above baseline expected in this adolescent population. The significance of these changes in regard to long-term bone health and future fracture risk is unknown [see Warnings and Precautions (5.12)].

In an open-label clinical trial (N=217) of a single course of therapy with isotretinoin for adolescents with severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change >-4% and total hip change >-5%) or were increased in the majority of patients. One patient had a decrease in lumbar spine bone mineral density >4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density >4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone mineral density >5% based on unadjusted data. Twenty-one (10.6%) patients had decreases in total hip bone mineral density >5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up trials performed in 8 of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in 5 patients at the lumbar spine, while the other 3 patients had lumbar spine bone density measurements below baseline values. Total hip bone mineral densities remained below baseline (range −1.6% to −7.6%) in 5 of 8 patients (62.5%).

In a separate open-label extension trial of 10 patients, ages 13 to 18 years, who started a second course of isotretinoin 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25%.

There are spontaneous literature reports of premature epiphyseal closure in acne patients receiving recommended doses of isotretinoin. The effect of multiple courses of isotretinoin on epiphyseal closure is unknown. In a 20-week clinical trial that included 289 adolescents who had hand radiographs taken to assess bone age, a total of 9 patients had bone age changes that were clinically significant and for which a drug-related effect cannot be excluded [see Warnings and Precautions (5.12)].

Geriatric Use

Clinical trials of Absorica did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Although reported clinical experience has not identified differences in responses between elderly and younger patients, effects of aging might be expected to increase some risks associated with Absorica therapy.

Females of Reproductive Potential

All females of reproductive potential must comply with the iPLEDGE program requirements [see Warnings and Precautions (5.2)].

Pregnancy Testing

Absorica must only be prescribed to female patients who are known not to be pregnant as confirmed by a negative CLIA-certified laboratory conducted pregnancy test. Females of reproductive potential must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial Absorica prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for Absorica. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests must be at least 19 days.

Each month of continued Absorica therapy, patients must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated each month, in a CLIA-certified laboratory, prior to the female patient receiving each prescription. A pregnancy test must also be completed at the end of the entire course of isotretinoin therapy and 1 month after the discontinuation of isotretinoin.

Contraception

Females of reproductive potential must use 2 forms of effective contraception simultaneously, at least 1 of which must be a primary form, unless the patient commits to continuous abstinence from heterosexual contact, or the patient has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be post-menopausal. Patients must use 2 forms of effective contraception for at least 1 month prior to initiation of Absorica therapy, during Absorica therapy, and for 1 month after discontinuing Absorica therapy. Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) are an inadequate method of contraception during isotretinoin therapy [see Warnings and Precautions (5.3)].

Effective forms of contraception include both primary and secondary forms of contraception:

Any birth control method can fail. There have been reports of pregnancy from female patients who have used combination oral contraceptives, as well as transdermal patch/ injectable/ implantable/ vaginal ring hormonal birth control products; these pregnancies occurred while taking isotretinoin. These reports are more frequent for female patients who use only a single method of contraception. Therefore, it is critically important for females of reproductive potential use 2 effective forms of contraception simultaneously.

Using two forms of contraception simultaneously substantially reduces the chances that a female will become pregnant over the risk of pregnancy with either form alone. A drug interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for isotretinoin. Although hormonal contraceptives are highly effective, prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.

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 [see Drug Interactions (7.4)].

If the patient has unprotected heterosexual intercourse at any time 1 month before, during, or 1 month after therapy, she must:

If a pregnancy does occur during Absorica treatment, Absorica must be discontinued immediately. The patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or 1 month after Absorica therapy must be reported immediately to the FDA via the MedWatch number 1-800-FDA-1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com) [see Warnings and Precautions (5.2)].

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.

Absorica causes serious birth defects at any dosage (see Boxed CONTRAINDICATIONS AND WARNINGS). Females of reproductive potential who present with Absorica 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 Warnings and Precautions (5). 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 female patient who is or might become pregnant, for 1 month after the overdose. All patients with Absorica overdose should not donate blood for at least 1 month.

Absorica (isotretinoin) Capsules contain 10 mg, 20 mg, 25 mg, 30 mg, 35 mg or 40 mg of isotretinoin (a retinoid) in hard gelatin capsules for oral administration. In addition to the active ingredient, isotretinoin, each capsule contains the following inactive ingredients: propyl gallate, sorbitan monooleate, soybean oil and stearoyl polyoxylglycerides. The gelatin capsules contain the following dye systems:

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 with a molecular weight of 300.44.  It is practically insoluble in water, soluble in chloroform and sparingly soluble in alcohol and in isopropyl alcohol. The structural formula is:

Meets USP Dissolution Test 3.

A double-blind, randomized, parallel group trial (Study 1) was conducted in patients with severe recalcitrant nodular acne to evaluate the efficacy and safety of Absorica compared to a generic product of Accutane® under fed conditions. Enrolled patients had a weight of 40 to 110 kg with at least 10 nodular lesions on the face and/or trunk. A total of 925 patients were randomized 1:1 to receive Absorica or a generic product of Accutane® (isotretinoin). Study patients ranged from 12 to 54 years of age, were approximately 60% male, 40% female, and were 87% White, 4% Black, 6% Asian, and 3% Other. Patients were treated an initial dose of 0.5 mg/kg/day in two divided doses for the first 4 weeks followed by 1 mg/kg/day in two divided doses for the following 16 weeks.

Change from Baseline to Week 20 in total nodular lesion count and proportion of patients with at least a 90% reduction in total nodular lesion count from Baseline to Week 20 are presented in Table 3. Total nodular lesion counts by visit are presented in Figure 1.

Figure 1: Total Nodular (Facial and Truncal) Lesion Count by Visit in Study 1

Isotretinoin has been used to treat certain other skin conditions and some types of cancer. Talk to your doctor about the possible risks of using this medication for your condition.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Mechanism Of Action

ABSORICA is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1 mg/kg/day, inhibits sebaceous gland function and keratinization. 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 isotretinoin and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation. The exact mechanism of action of ABSORICA is unknown.

Pharmacodynamics

The pharmacodynamics of ABSORICA are unknown.

Pharmacokinetics

Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high-fat meal. ABSORICA is bioequivalent to Accutane® (isotretinoin) capsule when both drugs are taken with a high-fat meal. ABSORICA is more bioavailable than Accutane® (isotretinoin) capsules when both drugs are taken fasted; the AUC0-t of ABSORICA is approximately 83% greater than that of Accutane® . ABSORICA is therefore not interchangeable with generic products of Accutane® .

A single dose two-way crossover pharmacokinetic trial was conducted in 14 healthy adult male subjects comparing ABSORICA 40 mg (1 x 40 mg capsules), dosed under fasted and fed conditions. Under fed conditions after a high-fat meal, it was observed that the mean AUC0-t and Cmax were approximately 50% and 26% higher, than that observed under fasting conditions (Table 2). The observed elimination half-life (T½) was slightly lower in the fed state versus fasted. The time to peak concentration (Tmax) increased with food and this may be related to a longer absorption phase.

Table 2: Pharmacokinetic parameters of ABSORICA mean (%CV) following administration of 40 mg strength, N=14

Published clinical literature has shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin.

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

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 40 mg oral dose of ABSORICA to 57 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.

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.

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 40 mg (2 x 20 mg) oral dose of ABSORICA to 57 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (T½) of isotretinoin and 4-oxo-isotretinoin under fed states were 18 hours and 38 hours, respectively.

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. There were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and adult patients.

Animal Toxicology

In rats given 8 or 32 mg/kg/day of isotretinoin (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area) for 18 months or longer, the incidences of focal calcification, fibrosis and inflammation of the myocardium, calcification of coronary, pulmonary and mesenteric arteries, and metastatic calcification of the gastric mucosa were greater than in control rats of similar age. Focal endocardial and myocardial calcifications associated with calcification of the coronary arteries were observed in two dogs after approximately 6 to 7 months of treatment with isotretinoin at a dosage of 60 to 120 mg/kg/day (30 to 60 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area).

Clinical Studies

A double-blind, randomized, parallel group trial (Study 1) was conducted in patients with severe recalcitrant nodular acne to evaluate the efficacy and safety of ABSORICA compared to a generic product of Accutane® under fed conditions. Enrolled patients had a weight of 40 to 110 kg with at least 10 nodular lesions on the face and/or trunk. A total of 925 patients were randomized 1:1 to receive ABSORICA or a generic product of Accutane® (isotretinoin). Study patients ranged from 12 to 54 years of age, were approximately 60% male, 40% female, and were 87% White, 4% Black, 6% Asian, and 3% Other. Patients were treated an initial dose of 0.5 mg/kg/day in two divided doses for the first 4 weeks followed by 1 mg/kg/day in two divided doses for the following 16 weeks.

Change from Baseline to Week 20 in total nodular lesion count and proportion of patients with at least a 90% reduction in total nodular lesion count from Baseline to Week 20 are presented in Table 3. Total nodular lesion counts by visit are presented in Figure 1.

Table 3: Efficacy Results at Week 20 (Study 1)

Figure 1: Total Nodular (Facial and Truncal) Lesion Count by Visit in Study 1

Tell your doctor about all of the medicines you take including prescription and non-prescription medicines, vitamins and herbal supplements. Absorica and certain other medicines can interact with each other, sometimes causing serious side effects. Especially tell your doctor if you take:

• Vitamin A supplements. Vitamin A in high doses has many of the same side effects as Absorica. Taking both together may increase your chance of getting side effects.
• tetracycline antibiotics such as doxycycline, tetracycline, or minocycline (Minocin)
• progestin-only birth control pills (mini-pills) such as Camilla, and Norethindrone.
• Dilantin (phenytoin)
• corticosteroids such as dexamethasone, hydrocortisone, or fludrocortisone (Florinef)
• St. John’s wort

These medicines should not be used with Absorica unless your doctor tells you it is okay.

Know the medicines you take. Keep a list of them to show to your doctor and pharmacist. Do not take any new medicine without talking with your doctor.

Common side effects of Absorica include: cheilitis, epistaxis, hypertriglyceridemia, pruritus, xerosis cutis, decreased hdl cholesterol, increased liver enzymes, increased serum triglycerides, musculoskeletal signs and symptoms, dry nose, xeroderma, and xerostomia. Other side effects include: increased serum cholesterol. See below for a comprehensive list of adverse effects.

Applies to isotretinoin: oral capsule, oral capsule liquid filled

Along with its needed effects, isotretinoin (the active ingredient contained in Absorica) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking isotretinoin:

• Bone or joint pain
• burning, redness, itching, or other signs of eye inflammation
• difficulty with moving
• nosebleeds
• scaling, redness, burning, pain, or other signs of inflammation of the lips
• skin infection or rash

• Abdominal or stomach pain (severe)
• attempts at suicide or thoughts of suicide (usually stops after medicine is stopped)
• back pain
• bleeding or inflammation of the gums
• blurred vision or other changes in vision
• changes in behavior
• decreased vision after sunset or before sunrise (sudden or may continue after medicine is stopped)
• diarrhea (severe)
• headache (severe or continuing)
• mental depression
• nausea and vomiting
• pain or tenderness of the eyes
• pain, tenderness, or stiffness in the muscles (long-term treatment)
• rectal bleeding
• yellow eyes or skin

• Black, tarry stools
• bloating
• bloody cough
• bloody or cloudy urine
• bone pain, tenderness, or aching
• burning or stinging of the skin
• chest pain
• confusion
• constipation
• convulsions
• cough or hoarseness
• dark-colored urine
• decrease in height
• difficulty breathing
• difficulty speaking
• difficulty swallowing
• discharge from the eyes
• dizziness
• double vision
• ear pain
• excessive tearing
• fainting
• fast, irregular, pounding, or racing heartbeat or pulse
• fever with or without chills
• fractures and/or delayed healing
• heartburn
• high blood pressure
• hives or skin rash
• inability to move the arms, legs, or facial muscles
• inability to speak
• indigestion
• inflamed tissue from infection
• irregular yellow patch or lump on the skin
• irritation
• joint pain, redness, stiffness, or swelling
• lack or slowing of normal growth in children
• loosening of the fingernails
• loss of appetite
• loss of bladder control
• loss or change in hearing
• muscle cramps, spasms, or weakness
• pain in the ribs, arms, or legs
• pain or burning in the throat
• pain or tenderness around the eyes and cheekbones
• painful cold sores or blisters on the lips, nose, eyes, or genitals
• painful or difficult urination
• pains in the chest, groin, or legs, especially calves of the legs
• pains in the stomach, side, or abdomen, possibly radiating to the back
• pale skin
• pinpoint red spots on the skin
• redness or soreness around the fingernails
• redness, soreness, or itching skin
• sensitivity of the eyes to sunlight
• sneezing
• sores, ulcers, or white spots on the lips or tongue or inside the mouth
• stuffy or runny nose
• sudden loss of consciousness
• sudden loss of coordination
• sudden onset of severe acne on the chest and trunk
• sudden onset of slurred speech
• swelling of the eyelids, face, lips, hands, lower legs, or feet
• swollen, painful or tender lymph glands in the neck, armpit, or groin
• tightness in the chest
• unusual bleeding or bruising
• unusual weight gain or loss
• use of extreme physical or emotional force
• watery or bloody diarrhea

Some side effects of isotretinoin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Crusting of the skin
• difficulty in wearing contact lenses (may continue after medicine is stopped)
• dryness of the eyes (may continue after treatment is stopped)
• dryness of the mouth or nose
• dryness or itching of the skin
• headache (mild)
• increased sensitivity of the skin to sunlight
• peeling of the skin on palms of the hands or soles of the feet
• stomach upset
• thinning of the hair (may continue after treatment is stopped)

• Abnormal menstruation
• burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feeling
• changes in fingernails or toenails
• continuing ringing or buzzing, or other unexplained noise in the ears
• dandruff
• darkening of the skin
• flushing
• hair abnormalities
• hair loss
• increased hair growth, especially on the face
• lightening of normal skin color
• lightening of treated areas of dark skin
• nervousness
• oily skin
• redness of the face
• severe sunburn
• skin rash, encrusted, scaly and oozing
• stomach burning
• sweating
• trouble sleeping
• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
• unusually warm skin of the face
• voice changes

Use is contraindicated. Excreted into human milk: Unknown Excreted into animal milk: Data not available Comments: -This drug is highly lipophilic, and may be expressed into breastmilk. -The effects in the nursing infant are unknown.