Zenatane

Mechanism of Action

Retinoid; inhibits sebaceous gland function and keratinization; clinical improvement of nodular acne associated with sebum secretion reduction

Absorption

Bioavailability: Low

Peak plasma time

• 5.3 hr (fed); 3.2 hr (fasted)
• Absorica: 6.4 hr (fed); 2.9 hr (fasted)

Peak plasma concentration

• 862 ng/mL (fed); 301 ng/mL (fasted)
• Absorica: 395 ng/mL (fed); 314 ng/mL (fasted)

AUC

• 10,004 ng•hr/mL (fed): 3703 ng•hr/mL (fasted)
• Absorica: 6095 ng•hr/mL (fed); 4055 ng•hr/mL (fasted); AUC (fasted state) greater than Accutane, and therefore not interchangeable with generic products

Distribution

Protein bound: 99.9% (primarily albumin)

Metabolism

Metabolized by liver oxidation via hepatic isoenzymes CYP2B6, CYP2C8/9, and CYP3A4

Metabolites: 4-oxo-isotretinoin, retinoic acid (tretinoin), 4-oxo-retinoic acid

Elimination

Half-life: 10-20 hr; 22-24 hr (Absorica)

Clinical Trials and Post-marketing Surveillance

The adverse reactions listed below reflect the experience from investigational studies of Zenatane, and the post-marketing experience. The relationship of some of these events to Zenatane therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving Zenatane 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 xanthomas7,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)

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

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

REFERENCES

7. Dicken CH, Connolly SM. Eruptive xanthomas associated with isotretinoin (13-cis-retinoic acid). Arch Dermatol 116:951-952, 1980.

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.

Zenatane falls into category X. Zenatane must not be taken by patients who are pregnant or who may become pregnant. There is a high risk that Zenatane 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 Zenatane and that women do not become pregnant while taking Zenatane. All patients, including women who cannot become pregnant and men, can get Zenatane 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 Zenatane, 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 Zenatane 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 Zenatane
• while taking Zenatane
• for 1 month after stopping Zenatane

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

Do not breastfeed while taking Zenatane and for one month after stopping Zenatane. It is not known if Zenatane is excreted in human breast milk or if it will harm your nursing baby. Tell your doctor if you are breastfeeding before you receive Zenatane.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on your weight.

The recommended dosage range for Zenatane (isotretinoin) is 0.5 to 1 mg/kg/day given in two divided doses.

Some patients may require dose adjustments up to 2 mg/kg/day.

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

CONTRAINDICATIONS AND WARNINGS

Zenatane™ 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 Zenatane™ 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 Zenatane™ 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 Zenatane™ , Zenatane™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 Zenatane™ teratogenicity and to minimize fetal exposure, Zenatane™ is approved for marketing only under a special restricted distribution program approved by the Food and Drug Administration. This program is called iPLEDGE™. Zenatane™ must only be prescribed by prescribers who are registered and activated with the iPLEDGE program. Zenatane™ 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.

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.

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.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Dry mouth.
• Dry eyes.
• Dry skin.
• Dry lips.
• Nose irritation.
• Change in how contact lenses feel in the eyes.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• Store at room temperature.
• Protect from light.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Isotretinoin USP, a retinoid, is available as Zenatane™ (isotretinoin capsules USP) in 10 mg, 20 mg, 30 mg and 40 mg soft gelatin capsules for oral administration. Each capsule contains butylated hydroxyanisole, edetate disodium, ferric oxide red, ferric oxide yellow, hydrogenated vegetable oil  (Type-I and Type-II), medium chain triglyceride, refined soybean oil and white wax. Gelatin capsules contain gelatin, glycerin, methyl paraben, propyl paraben, lake blend blue(LB-332) containing D&C Yellow No.10, FD&C Blue No.1 (for 10 mg), lake blend red (LB-1574) containing D&C Red No.27, D&C Red No.30 (for 20 mg), lake blend green (LB-333) containing D&C Yellow No.10, FD&C Blue No.1 (for 40 mg), lake blend white (TLB-1774) containing FD&C Blue No.2, titanium dioxide, opacode black S-1-27794 containing iron oxide black, N-butyl alcohol, propylene glycol, industrial methylene spirit and shellac (for 10 mg, 20 mg and 40 mg) and opacode black S-1-17823 containing iron oxide black, N-butyl alcohol, propylene glycol, ammonium hydroxide and shellac (for 30 mg).

Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A). It is a yellow or light orange crystalline powder with a molecular weight of 300.44. It is practically insoluble in water, soluble in chloroform; sparingly soluble in  alcohol, in isopropyl alcohol and in polyethylene glycon 400. The structural formula is:

Meets USP Dissolution Test 5.

Isotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1 mg/kg/day (see DOSAGE ANDADMINISTRATION), 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 Zenatane™, 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 Zenatane™ 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 Zenatane™ 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, Zenatane™ should always be taken with food (see DOSAGEAND 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 Isotretinoin Mean (%CV), N=74)

*Eating a standardized high fat meal

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-oxotretinoin). 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 Zenatane™ 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 Zenatane™ to 74 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (t1/2) of isotretinoin and 4-oxo-isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.9 to 5.43 in patients with cystic acne.

Special Patient Populations

Pediatric Patients

The pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients (≥18 years) who received Zenatane™ 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*

*The single and multiple dose data in this table were obtained following a non-standardized meal that is not comparable to the high-fat meal that was used in the study in Table 2.

†Median (range)

In pediatric patients (12 to 15 years), the mean ± SD elimination half-lives (t1/2) of isotretinoin and 4-oxo-isotretinoin were 15.7 ± 5.1 hours and 23.1 ± 5.7 hours, respectively. The accumulation ratios of isotretinoin ranged from 0.46 to 3.65 for pediatric patients.