Isotretinoin Capsules

Name: Isotretinoin Capsules

Isotretinoin Capsules Description

Isotretinoin USP, a retinoid, is available in 10 mg, 20 mg, 30 mg and 40 mg soft 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

Each capsule contains the following inactive ingredients: butylated hydroxyanisole, edetate disodium dihydrate, gelatin, glycerin, hydrogenated vegetable oil, purified water, soybean oil, titanium dioxide,  and white wax (beeswax).

In addition, the 10 mg capsule contains iron oxide black and iron oxide yellow. The 20 mg capsule contains iron oxide black, iron oxide red and iron oxide yellow. The 30 mg capsule contains FD&C yellow #6 aluminum lake. The 40 mg capsule contains FD&C yellow #6 aluminum lake.

Product meets USP Dissolution Test 4.

Isotretinoin Capsules - Clinical Pharmacology

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 isotretinoin, and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.1

Pharmacokinetics

Absorption

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 isotretinoin 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 isotretinoin 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, isotretinoin 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 Isotretinoin Mean (%CV), N = 74

Isotretinoin
2 x 40 mg Capsules

AUCo-∞

(ng•hr/mL)

Cmax

(ng/mL)

Tmax

(hr)

(hr)

Fed*

10,004 (22%)

862 (22%)

5.3 (77%)

21 (39%)

Fasted

3,703 (46%)

301 (63%)

3.2 (56%)

21 (30%)

* Eating a standardized high fat meal


Distribution

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


Metabolism

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.

Elimination

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 (t½) 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

 

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 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*

Parameter

Isotretinoin (Single Dose)

Isotretinoin (Steady-State)

Cmax (ng/mL)

573.25 (278.79)

731.98 (361.86)

AUC(0 to 12) (ng·hr/mL)

3033.37 (1394.17)

5082 (2184.23)

AUC(0 to 24) (ng·hr/mL)

6003.81 (2885.67)

--

Tmax (hr)†

6 (1 to 24.6)

4 (0 to 12)

Cssmin (ng/mL)

--

352.32 (184.44)

T½ (hr)

--

15.69 (5.12)

CL/F (L/hr)

--

17.96 (6.27)

*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 (t½) 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.

Warnings

Psychiatric Disorders

Isotretinoin may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide and aggressive and/or violent behaviors. No mechanism of action has been established for these events (see ADVERSE REACTIONS, Psychiatric). Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin. Prescribers should be alert to the warning signs of psychiatric disorders to guide patients to receive the help they need. Therefore, 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 may be necessary. Signs and symptoms of depression, as described in the brochure (“Recognizing Psychiatric Disorders in Adolescents and Young Adults”), include sad mood, hopelessness, feelings of guilt, worthlessness or helplessness, loss of pleasure or interest in activities, fatigue, difficulty concentrating, change in sleep pattern, change in weight or appetite, suicidal thoughts or attempts, restlessness, irritability, acting on dangerous impulses and persistent physical symptoms unresponsive to treatment. Patients should stop isotretinoin and the patient or a family member should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression, without waiting until the next visit. Discontinuation of isotretinoin therapy may be insufficient; further evaluation may be necessary. While such monitoring may be helpful, it may not detect all patients at risk. Patients may report mental health problems or family history of psychiatric disorders. These reports should be discussed with the patient and/or the patient’s family. A referral to a mental health professional may be necessary. The physician should consider whether isotretinoin therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of isotretinoin therapy.

 

Pseudotumor Cerebri

 

Isotretinoin use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines. Concomitant treatment with tetracyclines should therefore be avoided. Early signs and symptoms of pseudotumor cerebri 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, Neurological).


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 events may be serious and result in death, life-threatening events, hospitalization or disability. Patients should be monitored closely for severe skin reactions, and discontinuation of isotretinoin should be considered if warranted.

Pancreatitis


Acute pancreatitis has been reported in patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. Isotretinoin should be stopped if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur.


Lipids

Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with isotretinoin. Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving isotretinoin in clinical trials. In addition, approximately 15% developed a decrease in high-density lipoproteins and about 7% showed an increase in cholesterol levels. In clinical trials, the effects on triglycerides, HDL and cholesterol were reversible upon cessation of isotretinoin therapy. Some patients have been able to reverse triglyceride elevation by reduction in weight, restriction of dietary fat and alcohol, and reduction in dose while continuing isotretinoin.5

Blood lipid determinations should be performed before isotretinoin is given and then at intervals until the lipid response to isotretinoin is established, which usually occurs within 4 weeks. Especially careful consideration must be given to risk/benefit for patients who may be at high risk during isotretinoin therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If isotretinoin therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended (see PRECAUTIONS, Laboratory Tests).

The cardiovascular consequences of hypertriglyceridemia associated with isotretinoin are unknown.

Animal Studies

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

Hearing Impairment

Impaired hearing has been reported in patients taking isotretinoin; in some cases, the hearing impairment has been reported to persist after therapy has been discontinued. Mechanism(s) and causality for this event have not been established. Patients who experience tinnitus or hearing impairment should discontinue isotretinoin treatment and be referred for specialized care for further evaluation (see ADVERSE REACTIONS, Special Senses).

Hepatotoxicity

Clinical hepatitis considered to be possibly or probably related to isotretinoin therapy has been reported. Additionally, mild to moderate elevations of liver enzymes have been observed in approximately 15% of individuals treated during clinical trials, some of which normalized with dosage reduction or continued administration of the drug. If normalization does not readily occur or if hepatitis is suspected during treatment with isotretinoin, the drug should be discontinued and the etiology further investigated.

Inflammatory Bowel Disease

Isotretinoin has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. In some instances, symptoms have been reported to persist after isotretinoin treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue isotretinoin immediately (see ADVERSE REACTIONS, Gastrointestinal).

Skeletal

Bone Mineral Density

Effects of multiple courses of isotretinoin on the developing musculoskeletal system are unknown. There is some evidence that long-term, high dose, or multiple courses of therapy with isotretinoin have more of an effect than a single course of therapy on the musculoskeletal system. In an open-label clinical trial (N = 217) of a single course of therapy with isotretinoin for severe recalcitrant nodular acne, bone density measurements at several skeletal sites were not significantly decreased (lumbar spine change > -4% and total hip change > -5%) or were increased in the majority of patients. One patient had a decrease in lumbar spine bone mineral density >4% based on unadjusted data. Sixteen (7.9%) patients had decreases in lumbar spine bone mineral density > 4%, and all the other patients (92%) did not have significant decreases or had increases (adjusted for body mass index). Nine patients (4.5%) had a decrease in total hip bone mineral density > 5% based on unadjusted data. Twenty one (10.6%) patients had decreases in total hip bone mineral density > 5%, and all the other patients (89%) did not have significant decreases or had increases (adjusted for body mass index). Follow-up studies performed in eight of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in five patients at the lumbar spine, while the other three patients had lumbar spine bone density measurements below baseline values. Total hip bone mineral densities remained below baseline (range –1.6% to –7.6%) in five of eight patients (62.5%).


In a separate open-label extension study of ten patients, ages 13 to 18 years, who started a second course of isotretinoin 4 months after the first course, two patients showed a decrease in mean lumbar spine bone mineral density up to 3.25% (see PRECAUTIONS, Pediatric Use).

Spontaneous reports of osteoporosis, osteopenia, bone fractures and delayed healing of bone fractures have been seen in the isotretinoin population. While causality to isotretinoin has not been established, an effect cannot be ruled out. Longer term effects have not been studied. It is important that isotretinoin be given at the recommended doses for no longer than the recommended duration.

Hyperostosis
A high prevalence of skeletal hyperostosis was noted in clinical trials for disorders of keratinization with a mean dose of 2.24 mg/kg/day. Additionally, skeletal hyperostosis was noted in six of eight patients in a prospective study of disorders of keratinization.6 Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in prospective studies of nodular acne patients treated with a single course of therapy at recommended doses. The skeletal effects of multiple isotretinoin treatment courses for acne are unknown.

In a clinical study of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, hyperostosis was not observed after 16 to 20 weeks of treatment with approximately 1 mg/kg/day of isotretinoin given in two divided doses. Hyperostosis may require a longer time frame to appear. The clinical course and significance remain unknown.

Premature Epiphyseal Closure

There are spontaneous reports of premature epiphyseal closure in acne patients receiving recommended doses of isotretinoin. The effect of multiple courses of isotretinoin on epiphyseal closure is unknown.

Vision Impairment

Visual problems should be carefully monitored. All isotretinoin patients experiencing visual difficulties should discontinue isotretinoin treatment and have an ophthalmological examination (see ADVERSE REACTIONS, Special Senses).

Corneal Opacities

Corneal opacities have occurred in patients receiving isotretinoin for acne and more frequently when higher drug dosages were used in patients with disorders of keratinization. The corneal opacities that have been observed in clinical trial patients treated with isotretinoin have either completely resolved or were resolving at follow-up 6 to 7 weeks after discontinuation of the drug (see ADVERSE REACTIONS, Special Senses).

Decreased Night Vision

Decreased night vision has been reported during isotretinoin therapy and in some instances the event has persisted after therapy was discontinued. Because the onset in some patients was sudden, patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night.

Isotretinoin Capsules Dosage and Administration

Isotretinoin Capsules should be administered with a meal (see PRECAUTIONS, Information for Patients).

The recommended dosage range for Isotretinoin Capsules is 0.5 to 1 mg/kg/day given in two divided doses with food for 15 to 20 weeks. In studies comparing 0.1, 0.5 and 1 mg/kg/day,8 it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects – 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 dose adjustments up to 2 mg/kg/day, as tolerated. Failure to take Isotretinoin Capsules with food will significantly decrease absorption. Before upward dose adjustments are made, the patients should be questioned about their compliance with food instructions.

The safety of once daily dosing with Isotretinoin Capsules has not been established. Once daily dosing is not recommended.


If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated. 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 doses, has not been studied, and is not recommended. It is important that Isotretinoin Capsules be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Isotretinoin Capsules on bone loss is unknown (see WARNINGS, Skeletal, Bone Mineral Density, Hyperostosis and Premature Epiphyseal Closure).

Contraceptive measures must be followed for any subsequent course of therapy (see PRECAUTIONS).


Table 4. Isotretinoin Capsules Dosing by Body Weight (Based on Administration With Food)

Body Weight

Total mg/day

kilograms

pounds

0.5 mg/kg

1 mg/kg

2 mg/kg*

40

88

20

40

80

50

110

25

50

100

60

132

30

60

120

70

154

35

70

140

80

176

40

80

160

90

198

45

90

180

100

220

50

100

200

* See DOSAGE AND ADMINISTRATION: the recommended dosage range is 0.5 to 1 mg/kg/day.

INFORMATION FOR PHARMACISTS

Access the iPLEDGE Program system via the internet (www.ipledgeprogram.com), telephone (1-866-495-0654) or through electronic telecommunication verification (via submission of an isotretinoin prescription claim) to obtain an authorization and the “do not dispense to patient after” date. Isotretinoin Capsules must only be dispensed in no more than a 30 day supply.


REFILLS REQUIRE A NEW PRESCRIPTION AND A NEW AUTHORIZATION FROM THE iPLEDGE SYSTEM.


An Isotretinoin Capsules Medication Guide must be given to the patient each time Isotretinoin Capsules are dispensed, as required by law. This Isotretinoin Capsules Medication Guide is an important part of the risk management program for 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:

    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 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.
  • 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: __________

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 the appropriate educational materials, such as the 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.

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