Claravis Capsules

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 serious birth defects at any dosage (see BOXED CONTRAINDICATIONS AND WARNINGS). Females of reproductive potential 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 female 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.

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

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 (Cmax) 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 (Tmax) 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.

Table 2: Pharmacokinetic Parameters of Is otretinoin Mean (%CV), N = 74

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 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.

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 (tmax) 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

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.

Table 3: Pharmacokinetic Parameters of Isotretinoin Following Single and Multiple Dose Administration in Pediatric Patients, 12 to 15 Years of Age Mean (± SD), N = 38

In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t½) of isotretinoin and 4-oxoisotretinoin 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.

REFERENCES

1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med 300:329-333, 1979.

To be completed by the patient (and her parent or guardian* if patient is under age 18) and signed by her doctor.

Read each item below and initial in the space provided to show that you understand each item and agree to follow your doctor's instructions. Do not sign this consent and do not take isotretinoin if there is anything that you do not understand.

*A parent or guardian of a minor patient (under age 18) must also read and initial each item before signing the consent.

_______________________________________________(Patient's Name)

1. I understand that there is a very high chance that my unborn baby could have severe birth defects if I am pregnant or become pregnant while taking isotretinoin. This can happen with any amount and even if taken for short periods of time. This is why I must not be pregnant while taking isotretinoin.

Initial: __________

2. I understand that I must not get pregnant one month before, during the entire time of my treatment, and for one month after the end of my treatment with isotretinoin.

Initial: __________

3. I understand that I must avoid sexual intercourse completely, or I must use two separate, effective forms of birth control (contraception) at the s ame time. The only exceptions are if I have had surgery to remove the uterus (a hysterectomy) or both of my ovaries (bilateral oophorectomy), or my doctor has medically confirmed that I am postmenopausal.

Initial: __________

4. I understand that hormonal birth control products are among the most effective forms of birth control. Combination birth control pills and other hormonal products include skin patches, shots, under-the-skin implants, vaginal rings, and intrauterine devices (IUDs). Any form of birth control can fail. That is why I must use two different birth control methods at the same time, starting one month before, during, and for one month after stopping therapy every time I have sexual intercourse, even if one of the methods I choose is hormonal birth control.

Initial: __________

5. I understand that the following are effective forms of birth control:

Primary forms

• tubal sterilization (tying my tubes)
• partner's vasectomy
• intrauterine device
• hormonal (combination birth control pills, skin patches, shots, under-the skin implants, or vaginal ring.

Secondary forms

Barrier forms:

• male latex condom with or without spermicide
• diaphragm with spermicide
• cervical cap with spermicide

Other:

• vaginal sponge (contains spermicide)

A diaphragm and cervical cap must each be used with spermicide, a special cream that kills sperm. I understand that at least one of my two forms of birth control must be a primary method.

Initial: __________

6. I will talk with my doctor about any medicines including herbal products I plan to take during my isotretinoin treatment because hormonal birth control methods may not work if I am taking certain medicines or herbal products.

Initial: __________

7. I may receive a free birth control counseling session from a doctor or other family planning expert. My isotretinoin doctor can give me an isotretinoin Patient Referral Form for this free consultation.

Initial: __________

8. I must begin using the birth control methods I have chosen as described above at least one month before I start taking isotretinoin.

Initial: __________

9. I cannot get my first prescription for isotretinoin unless my doctor has told me that I have two negative pregnancy test results. The first pregnancy test should be done when my doctor decides to prescribe isotretinoin. The second pregnancy test must be done in a lab during the first 5 days of my menstrual period right before starting isotretinoin therapy treatment or as instructed by my doctor. I will then have one pregnancy test; in a lab.

• every month during treatment
• at the end of treatment
• and 1 month after stopping treatment

I must not start taking isotretinoin until I am sure that I am not pregnant, have negative results from two pregnancy tests, and the second test has been done in a lab.

Initial:__________

10. I have read and understand the materials my doctor has provided to me, including The iPLEDGE Program Guide for Isotretinoin for Female Patients Who Can Get Pregnant, The iPLEDGE Birth Control Workbook and The iPLEDGE Program Patient Introductory Brochure. My doctor provided me and asked me to watch a video about birth control and a video about birth defects and isotretinoin.

I was told about a private counseling line that I may call for more information about birth control. I have received information on emergency birth control.

Initial: __________

11. I must stop taking isotretinoin right away and call my doctor if I get pregnant, miss my expected menstrual period, stop using birth control, or have sexual intercourse without using my two birth control methods at any time.

Initial: __________

12. My doctor provided me information about the purpose and importance of providing information to the iPLEDGE Program should I become pregnant while taking isotretinoin or within one month of the last dose. I understand that if I become pregnant, information about my pregnancy, my health, and my baby's health may be shared with the makers of isotretinoin, authorized parties who maintain the iPLEDGE Program for the makers of isotretinoin, and government health regulatory authorities.

Initial: __________

13. I understand that being qualified to receive isotretinoin in the iPLEDGE Program means that I:

• have had two negative urine or blood pregnancy tests before receiving the first isotretinoin prescription. The second test must be done in a lab. I must have a negative result from a urine or blood pregnancy test done in a lab repeated each month before I receive another isotretinoin prescription.
• have chosen and agreed to use two forms of effective birth control at the same time. At least one method must be a primary form of birth control, unless I have chosen never to have sexual contact with a male (abstinence), or I have undergone a hysterectomy. I must use two forms of birth control for at least one month before I start isotretinoin therapy, during therapy, and for one month after stopping therapy. I must receive counseling, repeated on a monthly basis, about birth control and behaviors associated with an increased risk of pregnancy.
• have signed a Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) that contains warnings about the chance of possible birth defects if I am pregnant or become pregnant and my unborn baby is exposed to isotretinoin.
• have been informed of and understand the purpose and importance of providing information to the iPLEDGE Program should I become pregnant while taking isotretinoin or within 1 month of the last dose.
• have interacted with the iPLEDGE Program before starting isotretinoin and on a monthly basis to answer questions on the program requirements and to enter my two chosen forms of birth control.

Initial: ______

My doctor has answered all my questions about isotretinoin and I understand that it is my responsibility not to get pregnant one month before, during isotretinoin treatment, or for one month after I stop taking is otretinoin.

Initial: ______

I now authorize my doctor ________________ to begin my treatment with isotretinoin.

Patient Signature:_____________________________________ Date: ______

Parent/Guardian Signature (if under age 18):________________ Date:______

Please print: Patient Name and Address_______________________________

______________________________ Telephone _______________________

I have fully explained to the patient, __________________, the nature and purpose of the treatment described above and the risks to females of reproductive potential. I have asked the patient if she has any questions regarding her treatment with isotretinoin and have answered those questions to the best of my ability.

Doctor Signature: __________________________________ Date: ______

PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT'S MEDICAL RECORD.

PLEASE PROVIDE A COPY TO THE PATIENT.

Patient Information/Informed Consent (for all patients )

To be completed by patient (and parent or guardian if patient is under age 18) and signed by the doctor.

Read each item below and initial in the space provided if you understand each item and agree to follow your doctor's instructions. A parent or guardian of a patient under age 18 must also read and understand each item before signing the agreement.

Do not sign this agreement and do not take isotretinoin if there is anything that you do not understand about all the information you have received about using isotretinoin.

1. I,___________________________________________(Patient's Name) understand that isotretinoin is a medicine used to treat severe nodular acne that cannot be cleared up by any other acne treatments, including antibiotics. In severe nodular acne, many red, swollen, tender lumps form in the skin. If untreated, severe nodular acne can lead to permanent scars.

Initials: __________

2. My doctor has told me about my choices for treating my acne.

Initials: __________

3. I understand that there are serious side effects that may happen while I am taking isotretinoin. These have been explained to me. These side effects include serious birth defects in babies of pregnant patients. [Note: There is a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant)].

Initials: __________

4. I understand 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 (see #7 below).

Initials: __________

5. Before I start taking isotretinoin, I agree to tell my doctor if I have ever had symptoms of depression (see #7 below), been psychotic, attempted suicide, had any other mental problems, or take medicine for any of these problems. Being psychotic means having a loss of contact with reality, such as hearing voices or seeing things that are not there.

Initials: __________

6. Before I start taking isotretinoin, I agree to tell my doctor if, to the best of my knowledge, anyone in my family has ever had symptoms of depression, been psychotic, attempted suicide, or had any other serious mental problems.

Initials: __________

7. Once I start taking isotretinoin, I agree to stop using isotretinoin and tell my doctor right away if any of the following signs and symptoms of depression or psychosis happen. I:

• Start to feel sad or have crying spells
• Lose interest in activities I once enjoyed
• Sleep too much or have trouble sleeping
• Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of violence)
• Have a change in my appetite or body weight
• Have trouble concentrating
• Withdraw from my friends or family
• Feel like I have no energy
• Have feelings of worthlessness or guilt
• Start having thoughts about hurting myself or taking my own life (suicidal thoughts)
• Start acting on dangerous impulses
• Start seeing or hearing things that are not real

Initials: __________

8. I agree to return to see my doctor every month I take isotretinoin to get a new prescription for isotretinoin, to check my progress, and to check for signs of side effects.

Initials: __________

9. Isotretinoin will be prescribed just for me - I will not share isotretinoin with other people because it may cause serious side effects, including birth defects.

Initials: __________

10. I will not give blood while taking isotretinoin or for one month after I stop taking isotretinoin. I understand that if someone who is pregnant gets my donated blood, her baby may be exposed to isotretinoin and may be born with serious birth defects.

Initials: __________

11. I have read the The iPLEDGE Program Patient Introductory Brochure, and other materials my provider provided me containing important safety information about isotretinoin. I understand all the information I received.

Initials: __________

12. My doctor and I have decided I should take isotretinoin. I understand that I must be qualified in the iPLEDGE Program to have my prescription filled each month. I understand that I can stop taking isotretinoin at any time. I agree to tell my doctor if I stop taking isotretinoin.

Initials: __________

I now allow my doctor _______________________ to begin my treatment with isotretinoin.

Patient Signature:_________________________________Date:____________________

Parent/Guardian Signature (if under age 18):____________________Date: ___________

Patient Name (print)__________________________________

Patient Address___________________________________ Telephone (____-____-____)

I have:

• fully explained to the patient, ______________________________, the nature and purpose of isotretinoin treatment, including its benefits and risks.
• provided the patient with the appropriate educational materials, The iPLEDGE Program Patient Introductory Brochure and asked the patient if he/she has any questions regarding his/her treatment with isotretinoin.
• answered those questions to the best of my ability.

Doctor Signature:_______________________________________Date:___________

PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT'S MEDICAL RECORD. PLEASE PROVIDE A COPY TO THE PATIENT.

MEDICATION GUIDE

CLARAVIS
(klar-uh-vis )
(isotretinoin) Capsules USP

Read the Medication Guide that comes with Claravis before you start taking it and each time you get a prescription. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about Claravis ?

• Claravis is used to treat a type of severe acne (nodular acne) that has not been helped by other treatments, including antibiotics.
• Because Claravis can cause birth defects, Claravis is only for patients who can understand and agree to carry out all of the instructions in the iPLEDGE Program.
• Claravis may cause serious mental health problems.

Birth defects (deformed babies ), loss of a baby before birth (miscarriage), death of the baby, and early (premature) births. Female patients who are pregnant or who plan to become pregnant must not take Claravis. Female patients must not get pregnant:

• for 1 month before starting Claravis
• while taking Claravis
• for 1 month after stopping Claravis.

If you get pregnant while taking Claravis, s top taking it right away and call your doctor. Doctors and patients should report all cases of pregnancy to:

• FDA MedWatch at 1-800-FDA-1088, and
• the iPLEDGE pregnancy registry at 1-866-495-0654

2. Serious mental health problems. Claravis may cause:

• depression
• psychosis (seeing or hearing things that are not real)
• suicide. Some patients taking Claravis 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.

Stop Claravis and call your doctor right away if you or a family member notices that you have any of the following signs and symptoms of depression or psychosis :

• start to feel sad or have crying spells
• lose interest in activities you once enjoyed
• sleep too much or have trouble sleeping
• become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of violence)
• have a change in your appetite or body weight
• have trouble concentrating
• withdraw from your friends or family
• feel like you have no energy
• have feelings of worthlessness or guilt
• start having thoughts about hurting yourself or taking your own life (suicidal thoughts)
• start acting on dangerous impulses
• start seeing or hearing things that are not real

After stopping Claravis, you may also need follow-up mental health care if you had any of these symptoms.

What is Claravis ?

Claravis is a medicine taken by mouth to treat the most severe form of acne (nodular acne) that cannot be cleared up by any other acne treatments, including antibiotics. Claravis can cause serious side effects (see “What is the most important information I should know about Claravis ?”). Claravis can only be:

• prescribed by doctors that are registered in the iPLEDGE Program
• dispensed by a pharmacy that is registered with the iPLEDGE Program
• given to patients who are registered in the iPLEDGE Program and agree to do everything required in the program

What is severe nodular acne?

Severe nodular acne is when many red, swollen, tender lumps form in the skin. These can be the size of pencil erasers or larger. If untreated, nodular acne can lead to permanent scars.

Who should not take Claravis ?

• Do not take Claravis if you are pregnant, plan to become pregnant, or become pregnant during Claravis treatment. Claravis causes severe birth defects. See “What is the most important information I should know about Claravis ?”
• Do not take Claravis if you are allergic to anything in it. See the end of this Medication Guide for a complete list of ingredients in Claravis.

What should I tell my doctor before taking Claravis ?

Tell your doctor if you or a family member has any of the following health conditions :

• mental problems
• asthma
• liver disease
• diabetes
• heart disease
• bone loss (osteoporosis) or weak bones
• an eating problem called anorexia nervosa (where people eat too little)
• food or medicine allergies

Tell your doctor if you are pregnant or breastfeeding. Claravis must not be used by women who are pregnant or breastfeeding.

Tell your doctor about all of the medicines you take including pres cription and nonprescription medicines, vitamins and herbal supplements. Claravis 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 Claravis. Taking both together may increase your chance of getting side effects.
• Tetracycline antibiotics. Tetracycline antibiotics taken with Claravis can increase the chances of getting increased pressure in the brain.
• Progestin-only birth control pills (mini-pills ). They may not work while you take Claravis. Ask your doctor or pharmacist if you are not sure what type you are using.
• Dilantin (phenytoin). This medicine taken with Claravis may weaken your bones.
• Corticosteroid medicines. These medicines taken with Claravis may weaken your bones.
• St. John's Wort. This herbal supplement may make birth control pills work less effectively.

These medicines should not be used with Claravisunless 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.

How should I take Claravis ?

• You must take Claravis exactly as prescribed. You must also follow all the instructions of the iPLEDGE Program. Before prescribing Claravis, your doctor will:
• explain the iPLEDGE Program to you
• have you sign the Patient Information/Informed Consent form (for all patients). Female patients who can get pregnant must also sign another consent form.

You will not be prescribed Claravis if you cannot agree to or follow all the instructions of the iPLEDGE Program.

• You will get no more than a 30 day supply of Claravis at a time. This is to make sure you are following the Claravis iPLEDGE Program. You should talk with your doctor each month about side effects.
• The amount of Claravis you take has been specially chosen for you. It is based on your body weight, and may change during treatment.
• Take Claravis 2 times a day with a meal, unless your doctor tells you otherwise. Swallow your Claravis capsules whole with a full glass of liquid. Do not chew or suck on the capsule. Claravis can hurt the tube that connects your mouth to your stomach (esophagus) if it is not swallowed whole.
• If you miss a dose, just skip that dose. Do not take 2 doses at the same time.
• If you take too much Claravis or overdose, call your doctor or poison control center right away.
• Your acne may get worse when you first start taking Claravis. This should last only a short while. Talk with your doctor if this is a problem for you.
• You must return to your doctor as directed to make sure you don't have signs of serious side effects. Your doctor may do blood tests to check for serious side effects from Claravis. Female patients who can get pregnant will get a pregnancy test each month.
• Female patients who can get pregnant must agree to use two separate forms of effective birth control at the same time one month before, while taking, and for one month after taking Claravis. You must access the iPLEDGE system to answer questions about the program requirements and to enter your two chosen forms of birth control. To access the iPLEDGE system, go to www.ipledgeprogram.com or call 1-866-495-0654.

You must talk about effective birth control methods with your doctor or go for a free visit to talk about birth control with another doctor or family planning expert. Your doctor can arrange this free visit, which will be paid for by the company that makes Claravis.

If you have sex at any time without using two forms of effective birth control, get pregnant, or miss your expected period, stop using Claravis and call your doctor right away.

What should I avoid while taking Claravis ?

• Do not get pregnant while taking Claravis and for one month after stopping Claravis. See “What is the most important information I should know about Claravis ?”
• Do not breastfeed while taking Claravis and for one month after stopping Claravis. We do not know if Claravis can pass through your milk and harm the baby.
• Do not give blood while you take Claravis and for one month after stopping Claravis. If someone who is pregnant gets your donated blood, her baby may be exposed to Claravis and may be born with birth defects.
• Do not take other medicines or herbal products with Claravis unless you talk to your doctor. See “What should I tell my doctor before taking Claravis ?”
• Do not drive at night until you know if Claravis has affected your vision. Claravis may decrease your ability to see in the dark.
• Do not have cosmetic procedures to smooth your s kin, including waxing, dermabrasion, or laser procedures, while you are using Claravis and for at least 6 months after you stop. Claravis can increase your chance of scarring from these procedures. Check with your doctor for advice about when you can have cosmetic procedures.
• Avoid sunlight and ultraviolet lights as much as possible. Tanning machines use ultraviolet lights. Claravis may make your skin more sensitive to light.
• Do not share Claravis with other people. It can cause birth defects and other serious health problems.

What are the possible side effects of Claravis ?

• Claravis can cause birth defects (deformed babies ), loss of a baby before birth (miscarriage), death of the baby, and early (premature) births. See “What is the most important information I should know about Claravis ?”
• Claravis may cause serious mental health problems. See “What is the most important information I should know about Claravis ?”
• serious brain problems. Claravis can increase the pressure in your brain. This can lead to permanent loss of eyesight and, in rare cases, death. Stop taking Claravis and call your doctor right away if you get any of these signs of increased brain pressure:
• bad headache
• blurred vision
• dizziness
• nausea or vomiting
• seizures (convulsions)
• stroke
• skin problems. Skin rash can occur in patients taking Claravis. In some patients a rash can be serious. Stop using Claravis and call your doctor right away if you develop conjunctivitis (red or inflamed eyes, like “pink eye”), a rash with a fever, blisters on legs, arms or face and/or sores in your mouth, throat, nose, eyes, or if your skin begins to peel.
• stomach area (abdomen) problems. Certain symptoms may mean that your internal organs are being damaged. These organs include the liver, pancreas, bowel (intestines), and esophagus (connection between mouth and stomach). If your organs are damaged, they may not get better even after you stop taking Claravis. Stop taking Claravis and call your doctor if you get:
• severe stomach, chest or bowel pain
• trouble swallowing or painful swallowing
• new or worsening heartburn
• diarrhea
• rectal bleeding
• yellowing of your skin or eyes
• dark urine
• bone and muscle problems. Claravis may affect bones, muscles, and ligaments and cause pain in your joints or muscles. Tell your doctor if you plan hard physical activity during treatment with Claravis. Tell your doctor if you get:
• back pain
• joint pain
• broken bone. Tell all healthcare providers that you take Claravis if you break a bone.

Stop Claravis and call your doctor right away if you have muscle weakness. Muscle weakness with or without pain can be a sign of serious muscle damage.

Claravis may stop long bone growth in teenagers who are still growing.

• hearing problems. Stop using Claravis and call your doctor if your hearing gets worse or if you have ringing in your ears. Your hearing loss may be permanent.
• vision problems. Claravis may affect your ability to see in the dark. This condition usually clears up after you stop taking Claravis, but it may be permanent. Other serious eye effects can occur. Stop taking Claravis and call your doctor right away if you have any problems with your vision or dryness of the eyes that is painful or constant. If you wear contact lenses, you may have trouble wearing them while taking Claravis and after treatment.
• lipid (fats and cholesterol in blood) problems. Claravis can raise the level of fats and cholesterol in your blood. This can be a serious problem. Return to your doctor for blood tests to check your lipids and to get any needed treatment. These problems usually go away when Claravis treatment is finished.
• serious allergic reactions. Stop taking Claravis and get emergency care right away if you develop hives, a swollen face or mouth, or have trouble breathing. Stop taking Claravis and call your doctor if you get a fever, rash, or red patches or bruises on your legs.
• blood sugar problems. Claravis may cause blood sugar problems including diabetes. Tell your doctor if you are very thirsty or urinate a lot.
• decreased red and white blood cells. Call your doctor if you have trouble breathing, faint, or feel weak.
• The common, less serious side effects of Claravis are dry skin, chapped lips, dry eyes, and dry nose that may lead to nosebleeds. Call your doctor if you get any side effect that bothers you or that does not go away.

These are not all of the possible side effects with Claravis. Your doctor or pharmacist can give you more detailed information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Claravis ?

• Store at 20° to 25°C (68° to 77°F). Protect from light.
• Keep Claravis and all medicines out of the reach of children.

General Information about Claravis.

Medicines are sometimes prescribed for conditions that are not mentioned in Medication Guides. Do not use Claravis for a condition for which it was not prescribed. Do not give Claravis to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Claravis. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Claravis that is written for healthcare professionals. You can also call iPLEDGE Program at 1-866-495-0654 or visit www.ipledgeprogram.com.

What are the ingredients in Claravis ?

Active Ingredient: Isotretinoin

Inactive Ingredients : 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.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

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).

Allergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS, Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss.

Palpitation, tachycardia, vascular thrombotic disease, stroke.

Hypertriglyceridemia (see WARNINGS, Lipids), alterations in blood sugar levels (see PRECAUTIONS, Laboratory Tests).

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.

Allergic reactions (see PRECAUTIONS, Hypersensitivity), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see PATIENT INFORMATION). See PRECAUTIONS, Laboratory Tests for other hematological parameters.

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 PATIENT INFORMATION), transient pain in the chest (see PATIENT INFORMATION), arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see PRECAUTIONS, Laboratory Tests).

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

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.

Abnormal menses.

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

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 PATIENT INFORMATION).

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 PATIENT INFORMATION), elevated sedimentation rates, elevated platelet counts, thrombocytopenia.

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

Read the entire FDA prescribing information for Claravis (Isotretinoin)

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© Claravis Patient Information is supplied by Cerner Multum, Inc. and Claravis Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.