Isotretinoin: Package Insert and Label Information

ISOTRETINOIN- isotretinoin capsule
Actavis Pharma, Inc.

1 INDICATIONS AND USAGE

Isotretinoin capsules are indicated for the treatment of severe recalcitrant nodular acne in non-pregnant patients 12 years of age and older with multiple inflammatory nodules with a diameter of 5 mm or greater. Because of significant adverse reactions associated with its use, isotretinoin capsules are reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics.

Limitations of Use:

If a second course of isotretinoin capsules therapy is needed, it is not recommended before a two-month waiting period because the patient’s acne may continue to improve following a 15 to 20-week course of therapy [see Dosage and Administration (2.2)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage of isotretinoin capsules is 0.5 to 1 mg/kg/day given in two divided doses with or without meals for 15 to 20 weeks (see Table 1).

To decrease the risk of esophageal irritation, instruct patients to swallow the capsules with a full glass of liquid. During treatment, the dosage may be adjusted according to response of the disease and/or adverse reactions, some of which may be dose-related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dosage adjustments up to 2 mg/kg/day for isotretinoin capsules in divided doses, as tolerated.

The safety and effectiveness of once daily dosing with isotretinoin capsules has not been established and is not recommended.

If a dose of isotretinoin capsules is missed, just skip that dose. Do not take two doses of isotretinoin capsules at the same time.

Table 1: Isotretinoin Capsules Daily Dosage by Body Weight¹

Body Weight	Total Daily Dosage (mg)1
	0.5 mg/kg	1 mg/kg	2 mg/kg
40 kg	20	40	80
50 kg	25	50	100
60 kg	30	60	120
70 kg	35	70	140
80 kg	40	80	160
90 kg	45	90	180
100 kg	50	100	200
1 Administer in two divided doses with or without meals

2.2 Duration of Use

A normal course of treatment is 15 to 20 weeks. If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, may discontinue isotretinoin capsules.

After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, may initiate a second course of isotretinoin capsules in patients who have completed skeletal growth. The use of another course of isotretinoin capsules therapy is not recommended before a two-month waiting period because the patient’s acne may continue to improve after a 15 to 20-week course of therapy. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth.

Long-term use of isotretinoin capsules, even in low dosages, has not been studied, and is not recommended. The effect of long-term use of isotretinoin capsules on bone loss is unknown [see Warnings and Precautions (5.12)].

2.3 Laboratory Testing Prior to Administration

The following laboratory testing must be completed prior to isotretinoin capsules use:

• Pregnancy testing: Ensure patient is not pregnant prior to administering isotretinoin capsules [see Contraindications (4) and Use in Specific Populations (8.1, 8.3)]
• A fasting lipid profile including triglycerides [see Warnings and Precautions (5.8, 5.15)].
• Liver function tests [see Warnings and Precautions (5.10, 5.15)].

3 DOSAGE FORMS AND STRENGTHS

Isotretinoin capsules, USP are available in 10 mg, 20 mg, 25 mg, 30 mg, 35 mg and 40 mg capsules.

• 10 mg capsules: White opaque/white opaque size 1 capsules imprinted with WPI and 2433 in black ink and filled with a yellow semi-solid and banded with a blue band.
• 20 mg capsules: White opaque/light yellow opaque size 0 capsules imprinted with WPI and 2434 in black ink and filled with a yellow semi-solid and banded with a blue band.
• 25 mg capsules: Light green opaque/light green opaque size 0 capsules imprinted with WPI and A128 in black ink and filled with a yellow semi-solid and banded with a blue band.
• 30 mg capsules: Orange opaque/orange opaque size 00 capsules imprinted with WPI and 2435 in black ink and filled with a yellow semi-solid and banded with a blue band.
• 35 mg capsules: Flesh opaque/flesh opaque size 00 capsules imprinted with WPI and A168 in black ink and filled with a yellow semi-solid and banded with a blue band.
• 40 mg capsules: Orange opaque/orange opaque size 00 capsules imprinted with WPI and 2436 in black ink and filled with a yellow semi-solid and banded with a blue band.

4 CONTRAINDICATIONS

4.1 Pregnancy

Isotretinoin is contraindicated in pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

4.2 Hypersensitivity

Isotretinoin is contraindicated in patients with hypersensitivity to isotretinoin (or Vitamin A, given the chemical similarity to isotretinoin) or to any of its components (anaphylaxis and other allergic reactions have occurred) [see Warnings and Precautions (5.14)].

5 WARNINGS AND PRECAUTIONS

5.1 Embryo-Fetal Toxicity

Isotretinoin is contraindicated in pregnancy [see Contraindications (4.1)]. Based on human data, isotretinoin can cause fetal harm when administered to a pregnant patient. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking any amount of isotretinoin even for short periods of time. Potentially any fetus exposed during pregnancy can be affected. There are no accurate means of determining prenatally whether an exposed fetus has been affected. Major congenital malformations, spontaneous abortions, and premature births have been documented following exposure to isotretinoin during pregnancy [see Use in Specific Populations (8.1)].

If a pregnancy occurs during isotretinoin treatment, discontinue isotretinoin immediately and refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or 1 month after isotretinoin therapy must be reported immediately to the FDA via the MedWatch telephone number 1-800-FDA-1088, and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).

Patients must be informed not to donate blood during isotretinoin therapy and for 1 month following discontinuation because the blood might be given to a pregnant patient whose fetus must not be exposed to isotretinoin.

Isotretinoin is available only through a restricted program under a REMS [see Warnings and Precautions (5.2)].

5.2 iPLEDGE Program

Isotretinoin is available only through a restricted program under a REMS called the iPLEDGE REMS because of the risk of embryo-fetal toxicity [see Warnings and Precautions (5.1)]. Notable requirements of the iPLEDGE REMS include the following:

• Prescribers must be certified with the program and comply with the following requirements:
  • Determine reproductive status of all patients prior to initiating treatment
  • Provide contraception counseling to patients who can get pregnant prior to and during treatment, or refer patients who can get pregnant to an expert for such counseling
  • Provide scheduled pregnancy testing, and verify and document the negative pregnancy test result prior to writing each prescription, for no more than a 30-day supply
• Patients who can become pregnant must be enrolled by signing an informed consent form and must comply with the following requirements
  • Comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3)]
  • Demonstrate comprehension of the safe-use conditions of the program every month
  • Obtain the prescription within 7 days of the pregnancy test collection
• Patients who cannot become pregnant must be enrolled by signing an informed consent form and must obtain the prescription within 30 days of the office visit
• Pharmacies that dispense isotretinoin must be certified by being registered and activated in the program, must only dispense to patients who are authorized to receive isotretinoin, and comply with the following requirements:
  • Only dispense a maximum of a 30-day supply with a Medication Guide.
  • Do not dispense refills. Dispense only with a new prescription and a new authorization from the program.
  • Return isotretinoin to inventory if patients do not obtain the prescription by the “Do Not Dispense To After” date
• Wholesalers and distributors must be registered with the program and must only distribute to certified pharmacies.

Further information, including a list of qualified pharmacies and distributors, is available at www.ipledgeprogram.com or 1-866-495-0654.

5.4 Psychiatric Disorders

Isotretinoin may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors [see Adverse Reactions (6)].

Healthcare providers should be alert to the warning signs of psychiatric disorders to help ensure patients receive the help they need (Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin). Prior to initiation of isotretinoin therapy, patients and family members should be asked about any history of psychiatric disorder, and at each visit during therapy patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation is necessary.

Patients should immediately stop isotretinoin and the patient (or caregiver) should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression. Discontinuation of isotretinoin may be insufficient; further evaluation may be necessary such as a referral to a mental healthcare professional.

5.5 Intracranial Hypertension (Pseudotumor Cerebri)

Isotretinoin use has been associated with cases of intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines. Concomitant treatment with tetracyclines should therefore be avoided with isotretinoin use. Early signs and symptoms of intracranial hypertension include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these symptoms should be screened for papilledema and, if present, they should be told to discontinue isotretinoin immediately and be referred to a neurologist for further diagnosis and care [see Adverse Reactions (6)].

5.6 Serious Skin Reactions

There have been postmarketing reports of erythema multiforme and severe skin reactions [e.g., Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)] associated with isotretinoin use. These reactions may be serious and result in death, life-threatening events, hospitalization, or disability. Patients should be monitored closely for severe skin reactions, and isotretinoin should be discontinued if they occur.

5.7 Pancreatitis

Acute pancreatitis has been reported with isotretinoin use in patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. If symptoms of pancreatitis occur, discontinue isotretinoin and seek medical attention.

5.8 Lipid Abnormalities

Elevations of serum triglycerides above 800 mg/dL have been reported with isotretinoin use. In clinical trials, marked elevations of serum triglycerides, decreases in high-density lipoproteins (HDL), and increases in cholesterol levels were reported in 25%, 15%, and 7% of patients treated with isotretinoin capsules, respectively. These lipid changes were reversible upon isotretinoin capsule cessation. Some patients have been able to reverse triglyceride elevation by reduction in weight and restriction of dietary fat and alcohol while continuing isotretinoin or through dosage reduction. The cardiovascular consequences of hypertriglyceridemia associated with isotretinoin are unknown.

Fasting lipid tests should be performed before isotretinoin treatment and then at intervals until the lipid response to isotretinoin is known, which usually occurs within 4 weeks. Careful consideration should be given to risk/benefit of isotretinoin in patients who are at higher risk of hypertriglyceridemia (e.g., patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If isotretinoin therapy is instituted in such patients, more frequent checks of serum values for lipids are recommended [see Warnings and Precautions (5.15)]. Isotretinoin should be stopped if hypertriglyceridemia cannot be controlled.