Amnesteem

Name: Amnesteem

Amnesteem Overdose

If you take too much this medication, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If this medication is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Other Requirements

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

What is Amnesteem (isotretinoin)?

Isotretinoin is a form of vitamin A. It reduces the amount of oil released by oil glands in your skin, and helps your skin renew itself more quickly.

Isotretinoin is used to treat severe nodular acne that has not responded to other treatments, including antibiotics.

Isotretinoin is available only from a certified pharmacy under a special program called iPLEDGE. You must be registered in the program and understand the risks and benefits of taking this medicine.

Isotretinoin may also be used for purposes not listed in this medication guide.

How should I take Amnesteem (isotretinoin)?

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Each prescription of isotretinoin must be filled within 7 days of the date it was written by your doctor. You will receive no more than a 30-day supply of isotretinoin at one time.

Always take isotretinoin with a full glass of water. Do not chew or suck on the capsule. Swallow it whole.

Take isotretinoin with food.

Use this medicine for the full prescribed length of time. Your acne may seem to get worse at first, but should then begin to improve.

While using isotretinoin, you may need frequent blood tests.

Never share this medicine with another person, even if they have the same symptoms you have.

Store at room temperature away from moisture, heat, and light.

Uses For Amnesteem

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.

Amnesteem - 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 Amnesteem, 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 Amnesteem 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 Amnesteem 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, Amnesteem 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
* Eating a standardized high fat meal

Amnesteem

2 x 40 mg

Capsules

AUC0-∞

(ng•hr/mL)

Cmax

(ng/mL)

Tmax

(hr)

t1/2

(hr)

Fed*

10,004 (22%)

862 (22%)

5.3 (77%)

21 (39%)

Fasted

3,703 (46%)

301 (63%)

3.2 (56%)

21 (30%)

 

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 Amnesteem 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 Amnesteem to 74 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (t1/2) 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 Amnesteem 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)

Parameter

Isotretinoin

(Single Dose)

Isotretinoin

(Steady-State)

Cmax (ng/mL)

AUC(0 to 12) (ng.hr/mL)

AUC(0 to 24) (ng.hr/mL)

Tmax (hr)†

Cssmin (ng/mL)

T1/2 (hr)

CL/F (L/hr)

573.25 (278.79)

3033.37 (1394.17)

6003.81 (2885.67)

6 (1 - 24.6)

731.98 (361.86)

5082 (2184.23)

4 (0 to 12)

352.32 (184.44)

15.69 (5.12)

17.96 (6.27)

 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.

Indications and Usage for Amnesteem

Severe Recalcitrant Nodular Acne

Amnesteem is indicated for the treatment of severe recalcitrant nodular acne. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. “Severe,” by definition,2 means “many” as opposed to “few or several” nodules. Because of significant adverse effects associated with its use, Amnesteem should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, Amnesteem is indicated only for those female patients who are not pregnant, because Amnesteem can cause severe birth defects (see Boxed CONTRAINDICATIONS AND WARNINGS).

A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of disease in many patients.1,3,4 If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience has shown that patients may continue to improve while off Amnesteem. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth (see WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, and Premature Epiphyseal Closure).  

Amnesteem Dosage and Administration

Amnesteem should be administered with a meal (see PRECAUTIONS: Information for Patients).

The recommended dosage range for Amnesteem 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 Amnesteem 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 Amnesteem 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 Amnesteem, even in low doses, has not been studied, and is not recommended. It is important that Amnesteem be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Amnesteem 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. Amnesteem Dosing by Body Weight (Based on Administration with Food)
* See DOSAGE AND ADMINISTRATION: the recommended dosage range is 0.5 to 1 mg/kg/day.

Body Weight

Total mg/day

kilograms

pounds

0.5 mg/kg

1 mg/kg

2 mg/kg*

40

50

60

70

80

90

100

88

110

132

154

176

198

220

20

25

30

35

40

45

50

40

50

60

70

80

90

100

80

100

120

140

160

180

200

 INFORMATION FOR PHARMACISTS

Access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) to obtain an authorization and the “do not dispense to patient after” date. Amnesteem 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 Amnesteem Medication Guide must be given to the patient each time Amnesteem is dispensed, as required by law. This Amnesteem Medication Guide is an important part of the risk management program for the patient.

How is Amnesteem Supplied

Amnesteem (isotretinoin capsules, USP) contain 10 mg, 20 mg or 40 mg of isotretinoin, USP.

The 10 mg capsules are reddish brown and imprinted with I10. They are available as follows:

NDC 0378-6611-93
Cartons of 30 containing 3 Prescription Packs of 10 capsules

The 20 mg capsules are reddish brown and cream and imprinted with I20. They are available as follows:

NDC 0378-6612-93
Cartons of 30 containing 3 Prescription Packs of 10 capsules

The 40 mg capsules are orange-brown and imprinted with I40. They are available as follows:

NDC 0378-6614-93
Cartons of 30 containing 3 Prescription Packs of 10 capsules

Storage: Store at 68° to 77°F (20° to 25°C). [See USP Controlled Room Temperature.]

Protect from light.

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