Claravis

• TEVA Pharmaceuticals USA Inc.

• 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.

Claravis can cause serious side effects:

1) 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, stop 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

Other serious side effects:

• 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.

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

• Do not take Claravis if you are pregnant, plan to become pregnant or become pregnant during Claravis treatment. Claravis causes severe birth defects.
• Do not take Claravis if you are allergic to anything in it.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Claravis falls into category X. Claravis must not be taken by patients who are pregnant or who may become pregnant. There is a high risk that Claravis will cause birth defects (deformed babies), loss of a baby before birth (miscarriage), death of the baby and early (premature) births. See "Drug Precautions" section.

A program called iPLEDGE has been set up to make sure that pregnant women do not take Claravis and that women do not become pregnant while taking Claravis. All patients, including women who cannot become pregnant and men, can get Claravis only if they are registered with iPLEDGE, have a prescription from a doctor who is registered with iPLEDGE and fill the prescription at a pharmacy that is registered with iPLEDGE. 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. Female patients must not get pregnant:

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

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

CONTRAINDICATIONS AND WARNINGS

Claravis must not be used by female patients who are or may become pregnant. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking Claravis in any amount, even for short periods of time. Potentially any fetus exposed during pregnancy can be affected. There are no accurate means of determining whether an exposed fetus has been affected.

Birth defects which have been documented following Claravis exposure include abnormalities of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. Cases of IQ scores less than 85 with or without other abnormalities have been reported. There is an increased risk of spontaneous abortion and premature births have been reported.

Documented external abnormalities include: skull abnormality; ear abnormalities (including anotia, micropinna, small or absent external auditory canals); eye abnormalities (including microphthalmia); facial dysmorphia; cleft palate. Documented internal abnormalities include: CNS abnormalities (including cerebral abnormalities, cerebellar malformation, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular abnormalities; thymus gland abnormality; parathyroid hormone deficiency. In some cases death has occurred with certain of the abnormalities previously noted.

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

Special Prescribing Requirements

Because of Claravis’s teratogenicity and to minimize fetal exposure, Claravis is approved for marketing only under a special restricted distribution program approved by the Food and Drug Administration. This program is called iPLEDGE. Claravis must only be prescribed by prescribers who are registered and activated with the iPLEDGE program. Claravis must only be dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to patients who are registered and meet all the requirements of iPLEDGE.

Do not donate blood while taking isotretinoin and for at least 30 days after you stop taking it. Donated blood that is later given to a pregnant woman could lead to birth defects in her baby if the blood contains any level of isotretinoin.

Do not take a vitamin or mineral supplement that contains vitamin A.

While you are taking isotretinoin and for at least 6 months after your last dose: Do not use wax hair removers or have dermabrasion or laser skin treatments. Scarring may result.

Avoid exposure to sunlight or artificial UV rays (sunlamps or tanning beds). Isotretinoin can make your skin more sensitive to sunlight and sunburn may result.

Isotretinoin may impair your vision, especially at night. Be careful if you drive or do anything that requires you to see clearly.

Along with its needed effects, a medicine 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:

• 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 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

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

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

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.

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.

Common side effects of Claravis 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 Claravis) 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