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Isotretinoin

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Overview

What is Isotretinoin?

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:

CHO  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.



What does Isotretinoin look like?



What are the available doses of Isotretinoin?

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What should I talk to my health care provider before I take Isotretinoin?

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How should I use Isotretinoin?

Severe Recalcitrant Nodular Acne

Isotretinoin capsules are 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, means “many” as opposed to “few or several” nodules. . In addition, isotretinoin capsules are indicated only for those female patients who are not pregnant, because isotretinoin capsules can cause severe birth defects (see ).

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. 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 isotretinoin capsules. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth (see ).

Isotretinoin capsules should be administered with a meal (see ).

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, 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 recommended.

WARNINGS, Skeletal, Bone Mineral Density, Hyperostosis and Premature Epiphyseal Closure

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

DOSAGE AND ADMINISTRATION


What interacts with Isotretinoin?

Pregnancy


 


Teratogenic Effects


 


Category X


Boxed CONTRAINDICATIONS AND WARNINGS


Isotretinoin capsules are contraindicated in patients who are hypersensitive to this medication or to any of its components (see ).



What are the warnings of Isotretinoin?

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Psychiatric Disorders

 

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 ).

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

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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.

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 ).

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 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 ).

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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 ).

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%).

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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.

HyperostosisA 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. 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 ).

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 ).

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.


What are the precautions of Isotretinoin?

Isotretinoin must only be prescribed by prescribers who are registered and activated with the iPLEDGE Program. Isotretinoin must only be dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to patients who are registered meet all the requirements of iPLEDGE. Registered and activated pharmacies must receive isotretinoin only from wholesalers registered with iPLEDGE.

iPLEDGE Program requirements for wholesalers, prescribers and pharmacists are described below:

Wholesalers

For the purpose of the iPLEDGE Program, the term wholesaler refers to wholesaler, distributor and/or chain pharmacy distributor. To distribute isotretinoin, wholesalers must be registered with iPLEDGE and agree to meet all iPLEDGE requirements for wholesale distribution of isotretinoin products. Wholesalers must register with iPLEDGE by signing and returning the iPLEDGE wholesaler agreement that affirms they will comply with all iPLEDGE requirements for distribution of isotretinoin. These include:

Prescribers

To prescribe isotretinoin, the prescriber must be registered and activated with the pregnancy risk management program iPLEDGE. Prescribers can register by signing and returning the completed registration form. Prescribers can only activate their registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points:

To prescribe isotretinoin, the prescriber must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) to:

1. Register each patient in the iPLEDGE Program.

2. Confirm monthly that each patient has received counseling and education.

3. For

Isotretinoin must only be prescribed to female patients who are known not to be pregnant as confirmed by a negative CLIA-certified laboratory conducted pregnancy test.

Isotretinoin must only be dispensed by a pharmacy registered and activated with the pregnancy risk management program iPLEDGE and only when the registered patient meets all the requirements of the iPLEDGE Program. Meeting the requirements for a female of reproductive potential (FRP) signifies that she:

If the patient has unprotected heterosexual intercourse at any time one month before, during, or one month after therapy, she must:

Effective methods of contraception include both primary and secondary methods of contraception:

Primary methods

Secondary methods

Barrier:

Other:

Any birth control method can fail. There have been reports of pregnancy from female patients who have used oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products; these pregnancies occurred while these patients were taking isotretinoin. These reports are more frequent for female patients who use only a single method of contraception. Therefore, it is critically important that females of reproductive potential (FRP) use two effective methods of contraception simultaneously. Patients must receive written warnings about the rates of possible contraception failure (included in patient education kits).

Using two methods of contraception simultaneously substantially reduces the chances that a female will become pregnant over the risk of pregnancy with either method alone. A drug interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for isotretinoin (see ). Although hormonal contraceptives are highly effective, prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.

Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John’s Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort.

If a pregnancy does occur during isotretinoin treatment, isotretinoin must be discontinued immediately. The patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or one month after isotretinoin therapy must be reported immediately to the FDA via the MedWatch number 1-800-FDA-1088 and also the iPLEDGE Pregnancy Registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).

All Patients

Isotretinoin is contraindicated in female patients who are pregnant. To receive isotretinoin all patients must meet all of the following conditions:

Females of Reproductive

Potential (FRP)

Isotretinoin is contraindicated in female patients who are pregnant. In addition to the requirements for all patients described above, females of reproductive potential (FRP) must meet the following conditions:

Pharmacists

To dispense isotretinoin, pharmacies must be registered and activated with the pregnancy risk management program iPLEDGE.

The Responsible Site Pharmacist must register the pharmacy by signing and returning the completed registration form. After registration, the Responsible Site Pharmacist can only activate the pharmacy registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points:

To dispense isotretinoin, the pharmacist must:

Isotretinoin capsules must only be dispensed:

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

Isotretinoin capsules must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE Program. Only FDA-approved isotretinoin products must be distributed, prescribed, dispensed and used. Patients must obtain isotretinoin prescriptions only at US licensed pharmacies.

A description of the iPLEDGE Program educational materials available with iPLEDGE is provided below. The main goal of these educational materials is to explain the iPLEDGE Program requirements and to reinforce the educational messages.

General

  • Patients must be instructed to read the Medication Guide supplied as required by law when isotretinoin capsules are dispensed. The complete text of the Medication Guide is reprinted at the end of this document. For additional information, patients must also be instructed to read the iPLEDGE Program patient educational materials. All patients must sign the Patient Information/Informed Consent (for all patients) form.
  • Females of reproductive potential (FRP) must be instructed that they must not be pregnant when isotretinoin capsules therapy is initiated, and that they should use two methods of effective contraception simultaneously for one month before starting isotretinoin capsules, while taking isotretinoin capsules, and for one month after isotretinoin capsules have been stopped, unless they commit to continuous abstinence from heterosexual intercourse. They should also sign a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form prior to beginning isotretinoin capsules therapy. They should be given an opportunity to view the patient video and/or videos provided by the manufacturer to the prescriber. The video and/or videos include information about contraception, the most common reasons that contraception fails, and the importance of using two methods of effective contraception when taking teratogenic drugs and comprehensive information about types of potential birth defects which could occur if a female patient who is pregnant takes isotretinoin capsules at any time during pregnancy. Female patients should be seen by their prescribers monthly and have a urine or serum pregnancy test, in a CLIA-certified laboratory, performed each month during treatment to confirm negative pregnancy status before another isotretinoin capsules prescription is written (see and ).
  • Isotretinoin is found in the semen of male patients taking isotretinoin capsules, but the amount delivered to a female partner would be about one million times lower than an oral dose of 40 mg. While the no-effect limit for isotretinoin induced embryopathy is unknown, 20 years of postmarketing reports include four with isolated defects compatible with features of retinoid exposed fetuses; however two of these reports were incomplete and two had other possible explanations for the defects observed.
  • 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 treatment, patients and family members should be asked about any history of psychiatric disorder, and at each visit during treatment patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation may be necessary. 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 treatment 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.
  • Patients must be informed 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.
  • Patients must be informed that they must not share isotretinoin capsules with anyone else because of the risk of birth defects and other serious adverse events.
  • Patients must be informed not to donate blood during therapy and for one month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to isotretinoin capsules.
  • Patients should be reminded to take isotretinoin capsules with a meal (see ). To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid.
  • Patients should be informed that transient exacerbation (flare) of acne has been seen, generally during the initial period of therapy.
  • Wax epilation and skin resurfacing procedures (such as dermabrasion, laser) should be avoided during isotretinoin capsules therapy and for at least 6 months thereafter due to the possibility of scarring (see ).
  • Patients should be advised to avoid prolonged exposure to UV rays or sunlight.
  • Patients should be informed that they may experience decreased tolerance to contact lenses during and after therapy.
  • Patients should be informed that approximately 16% of patients treated with isotretinoin capsules in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of the drug. Transient pain in the chest has been reported less frequently. In the clinical trial, these symptoms generally cleared rapidly after discontinuation of isotretinoin capsules, but in some cases persisted (see ). There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity (see ).
  • Pediatric patients and their caregivers should be informed that approximately 29% (104/358) of pediatric patients treated with isotretinoin capsules developed back pain. Back pain was severe in 13.5% (14/104) of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 7.6% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of isotretinoin capsules. Consideration should be given to discontinuation of isotretinoin capsules if any significant abnormality is found.
  • Neutropenia and rare cases of agranulocytosis have been reported. Isotretinoin capsules should be discontinued if clinically significant decreases in white cell counts occur.
  • Patients should be advised that severe skin reactions (Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported in post-marketing data. Isotretinoin capsules should be discontinued if clinically significant skin reactions occur.


Although an effect of isotretinoin on bone loss is not established, physicians should use caution when prescribing isotretinoin to patients with a genetic predisposition for age-related osteoporosis, a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic corticosteroids and any anticonvulsant.

Patients may be at increased risk when participating in sports with repetitive impact where the risks of spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late adolescence are known. There are spontaneous reports of fractures and/or delayed healing in patients while on therapy with isotretinoin or following cessation of therapy with isotretinoin while involved in these activities. While causality to isotretinoin has not been established, an effect must not be ruled out.

Information for Patients

See and .

Hypersensitivity

Anaphylactic reactions and other allergic reactions have been reported. Cutaneous allergic reactions and serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement (including renal) have been reported. Severe allergic reaction necessitates discontinuation of therapy and appropriate medical management.

Drug Interactions

Vitamin A:

Tetracyclines:

Micro-dosed Progesterone Preparations:

PRECAUTIONS

Norethindrone/ethinyl estradiol:

St. John’s Wort:

Isotretinoin

use is associated with depression in some patients

WARNINGS, Psychiatric Disorders

ADVERSE REACTIONS, Psychiatric

Phenytoin:

in vitro

Systemic Corticosteroids:

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    Laboratory Tests

    - Females of reproductive potential (FRP) have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial isotretinoin prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for isotretinoin. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests must be at least 19 days.

    - For patients with regular menstrual cycles, the second pregnancy test must be done during the first 5 days of the menstrual period immediately preceding the beginning of isotretinoin therapy and after the patient has used two methods of contraception for 1 month.

    - For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done immediately preceding the beginning of isotretinoin therapy and after the patient has used two methods of contraception for 1 month.

    - Each month of therapy, patients must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated each month, in a CLIA-certified laboratory, prior to the female patient receiving each prescription.

    Lipids

    Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is recommended that these tests be performed at weekly or biweekly intervals until the lipid response to isotretinoin is established. The incidence of hypertriglyceridemia is one patient in four on isotretinoin therapy (see ).

    Liver Function Tests

    Since elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported, pretreatment and follow-up liver function tests should be performed at weekly or biweekly intervals until the response to isotretinoin has been established (see ).

    Glucose

    Some patients receiving isotretinoin have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during isotretinoin therapy, although no causal relationship has been established.

    Some patients undergoing vigorous physical activity while on isotretinoin therapy have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity. In a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, transient elevations in CPK were observed in 12% of patients, including those undergoing strenuous physical activity in association with reported musculoskeletal adverse events such as back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks. No cases of rhabdomyolysis were reported in this trial.

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    Carcinogenesis, Mutagenesis and Impairment of Fertility

    In male and female Fischer 344 rats given oral isotretinoin at dosages of 8 or 32 mg/kg/day (1.3 to 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area) for greater than 18 months, there was a dose-related increased incidence of pheochromocytoma relative to controls. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage in both sexes. The relatively high level of spontaneous pheochromocytomas occurring in the male Fischer 344 rat makes it an equivocal model for study of this tumor; therefore, the relevance of this tumor to the human population is uncertain.

    The Ames test was conducted with isotretinoin in two laboratories. The results of the tests in one laboratory were negative while in the second laboratory a weakly positive response (less than 1.6 x background) was noted in TA100 when the assay was conducted with metabolic activation. No dose-response effect was seen and all other strains were negative. Additionally, other tests designed to assess genotoxicity (Chinese hamster cell assay, mouse micronucleus test, D7 assay, clastogenesis assay with human-derived lymphocytes, and unscheduled DNA synthesis assay) were all negative.

    In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dosages of isotretinoin of 2, 8, or 32 mg/kg/day (0.3, 1.3, or 5.3 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area).

    In dogs, testicular atrophy was noted after treatment with oral isotretinoin for approximately 30 weeks at dosages of 20 or 60 mg/kg/day (10 or 30 times the recommended clinical dose of 1 mg/kg/day, respectively, after normalization for total body surface area). In general, there was microscopic evidence for appreciable depression of spermatogenesis but some sperm were observed in all testes examined and in no instance were completely atrophic tubules seen. In studies of 66 men, 30 of whom were patients with nodular acne under treatment with oral isotretinoin, no significant changes were noted in the count or motility of spermatozoa in the ejaculate. In a study of 50 men (ages 17 to 32 years) receiving isotretinoin therapy for nodular acne, no significant effects were seen on ejaculate volume, sperm count, total sperm motility, morphology or seminal plasma fructose.

    Pregnancy

    Teratogenic Effects

    Category X

    See .

    Nursing Mothers

    It is not known whether this drug is excreted in human milk. Because of the potential for adverse effects, nursing mothers should not receive isotretinoin.

    Pediatric Use

    The use of isotretinoin in pediatric patients less than 12 years of age has not been studied. The use of isotretinoin for the treatment of severe recalcitrant nodular acne in pediatric patients ages 12 to 17 years should be given careful consideration, especially for those patients where a known metabolic or structural bone disease exists (see ). Use of isotretinoin in this age group for severe recalcitrant nodular acne is supported by evidence from a clinical study comparing 103 pediatric patients (13 to 17 years) to 197 adult patients (≥18 years). Results from this study demonstrated that isotretinoin, at a dose of 1 mg/kg/day given in two divided doses, was equally effective in treating severe recalcitrant nodular acne in both pediatric and adult patients.

    In studies with isotretinoin, adverse reactions reported in pediatric patients were similar to those described in adults except for the increased incidence of back pain and arthralgia (both of which were sometimes severe) and myalgia in pediatric patients (see ).

    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 ).

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    Geriatric Use

    Clinical studies of isotretinoin did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Although reported clinical experience has not identified differences in responses between elderly and younger patients, effects of aging might be expected to increase some risks associated with isotretinoin therapy (see ).


    What are the side effects of Isotretinoin?

    Clinical Trials and Postmarketing Surveillance

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

    Body as a Whole

    Allergic reactions, including vasculitis, systemic hypersensitivity (see ), edema, fatigue, lymphadenopathy, weight loss.

    Cardiovascular

    Palpitation, tachycardia, vascular thrombotic disease, stroke.

    Endocrine/Metabolic

    Hypertriglyceridemia (see ), alterations in blood sugar levels (see ).

    Gastrointestinal

    Inflammatory bowel disease (see ), hepatitis (see ), pancreatitis (see ), bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms.

    Hematologic

    Allergic reactions (see ), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see ). See for other hematological parameters.

    Musculoskeletal

    Skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases in bone mineral density (see ), musculoskeletal symptoms (sometimes severe) including back pain, myalgia and arthralgia (see ), transient pain in the chest (see ), arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see ).

    Neurological

    Pseudotumor cerebri (see ), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness.

    Psychiatric

    Suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see ), emotional instability. Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.

    Reproductive System

    Abnormal menses.

    Respiratory

    Bronchospasms (with or without a history of asthma), respiratory infection, voice alteration.

    Skin and Appendages

    Acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas, 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 ), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see ).

    Special Senses:

    Hearing:

    Vision:

    Urinary System:

    Laboratory

    Elevation of plasma triglycerides (see ), 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 ).

    Elevation of fasting blood sugar, elevations of CPK (see ), hyperuricemia.

    Decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis; (see ), elevated sedimentation rates, elevated platelet counts, thrombocytopenia.

    White cells in the urine, proteinuria, microscopic or gross hematuria.


    What should I look out for while using Isotretinoin?

    Pregnancy

     

    Teratogenic Effects

     

    Category X

    Boxed CONTRAINDICATIONS AND WARNINGS

    Isotretinoin capsules are contraindicated in patients who are hypersensitive to this medication or to any of its components (see ).

    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 ). Prescribers should read the brochure, . 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 ).

    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

    In rare instances, fatal hemorrhagic pancreatitis has been reported.


    What might happen if I take too much Isotretinoin?

    The oral LD of isotretinoin is greater than 4000 mg/kg in rats and mice (>600 times the recommended clinical dose of 1 mg/kg/day after normalization of the rat dose for total body surface area and >300 times the recommended clinical dose of 1 mg/kg/day after normalization of the mouse dose for total body surface area) and is approximately 1960 mg/kg in rabbits (653 times the recommended clinical dose of 1 mg/kg/day after normalization for total body surface area). In humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness and ataxia. These symptoms quickly resolve without apparent residual effects.

    Isotretinoin causes serious birth defects at any dosage (see ). Females of reproductive potential (FRP) who present with isotretinoin overdose must be evaluated for pregnancy. Patients who are pregnant should receive counseling about the risks to the fetus, as described in the . Non-pregnant patients must be warned to avoid pregnancy for at least one month and receive contraceptive counseling as described in . Educational materials for such patients can be obtained by calling the manufacturer. Because an overdose would be expected to result in higher levels of isotretinoin in semen than found during a normal treatment course, male patients should use a condom, or avoid reproductive sexual activity with a female patient who is or might become pregnant, for one month after the overdose. All patients with isotretinoin overdose should not donate blood for at least one month.


    How should I store and handle Isotretinoin?

    Unopened vials of gemcitabine for injection, USP are stable until the expiration date indicated on the package when stored at controlled room temperature 20° to 25°C (68° to 77°F) and that allows for excursions between 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature] [].Isotretinoin capsules, USP are available as:Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1174-3Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1175-3Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1017-3Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1176-3Protect from light.Isotretinoin capsules, USP are available as:Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1174-3Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1175-3Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1017-3Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1176-3Protect from light.Isotretinoin capsules, USP are available as:Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1174-3Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1175-3Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1017-3Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1176-3Protect from light.Isotretinoin capsules, USP are available as:Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1174-3Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1175-3Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1017-3Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1176-3Protect from light.Isotretinoin capsules, USP are available as:Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1174-3Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1175-3Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1017-3Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1176-3Protect from light.Isotretinoin capsules, USP are available as:Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1174-3Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1175-3Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1017-3Cartons of 30 capsules containing 3 prescription blister packs of 10 capsules: NDC 69238-1176-3Protect from light.


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    Clinical Information

    Chemical Structure

    No Image found
    Clinical Pharmacology

    Isotretinoin is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1 mg/kg/day (see ), 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.

    Non-Clinical Toxicology
    Pregnancy

     

    Teratogenic Effects

     

    Category X

    Boxed CONTRAINDICATIONS AND WARNINGS

    Isotretinoin capsules are contraindicated in patients who are hypersensitive to this medication or to any of its components (see ).

    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 ). Prescribers should read the brochure, . 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 ).

    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

    In rare instances, fatal hemorrhagic pancreatitis has been reported.

    Laboratory Tests

    - Females of reproductive potential (FRP) have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial isotretinoin prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for isotretinoin. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests must be at least 19 days.

    - For patients with regular menstrual cycles, the second pregnancy test must be done during the first 5 days of the menstrual period immediately preceding the beginning of isotretinoin therapy and after the patient has used two methods of contraception for 1 month.

    - For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done immediately preceding the beginning of isotretinoin therapy and after the patient has used two methods of contraception for 1 month.

    - Each month of therapy, patients must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated each month, in a CLIA-certified laboratory, prior to the female patient receiving each prescription.

    Lipids

    Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is recommended that these tests be performed at weekly or biweekly intervals until the lipid response to isotretinoin is established. The incidence of hypertriglyceridemia is one patient in four on isotretinoin therapy (see ).

    Liver Function Tests

    Since elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported, pretreatment and follow-up liver function tests should be performed at weekly or biweekly intervals until the response to isotretinoin has been established (see ).

    Glucose

    Some patients receiving isotretinoin have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during isotretinoin therapy, although no causal relationship has been established.

    Isotretinoin must only be prescribed by prescribers who are registered and activated with the iPLEDGE Program. Isotretinoin must only be dispensed by a pharmacy registered and activated with iPLEDGE, and must only be dispensed to patients who are registered meet all the requirements of iPLEDGE. Registered and activated pharmacies must receive isotretinoin only from wholesalers registered with iPLEDGE.

    iPLEDGE Program requirements for wholesalers, prescribers and pharmacists are described below:

    Wholesalers

    For the purpose of the iPLEDGE Program, the term wholesaler refers to wholesaler, distributor and/or chain pharmacy distributor. To distribute isotretinoin, wholesalers must be registered with iPLEDGE and agree to meet all iPLEDGE requirements for wholesale distribution of isotretinoin products. Wholesalers must register with iPLEDGE by signing and returning the iPLEDGE wholesaler agreement that affirms they will comply with all iPLEDGE requirements for distribution of isotretinoin. These include:

    Prescribers

    To prescribe isotretinoin, the prescriber must be registered and activated with the pregnancy risk management program iPLEDGE. Prescribers can register by signing and returning the completed registration form. Prescribers can only activate their registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points:

    To prescribe isotretinoin, the prescriber must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) to:

    1. Register each patient in the iPLEDGE Program.

    2. Confirm monthly that each patient has received counseling and education.

    3. For

    Isotretinoin must only be prescribed to female patients who are known not to be pregnant as confirmed by a negative CLIA-certified laboratory conducted pregnancy test.

    Isotretinoin must only be dispensed by a pharmacy registered and activated with the pregnancy risk management program iPLEDGE and only when the registered patient meets all the requirements of the iPLEDGE Program. Meeting the requirements for a female of reproductive potential (FRP) signifies that she:

    If the patient has unprotected heterosexual intercourse at any time one month before, during, or one month after therapy, she must:

    Effective methods of contraception include both primary and secondary methods of contraception:

    Primary methods

    Secondary methods

    Barrier:

    Other:

    Any birth control method can fail. There have been reports of pregnancy from female patients who have used oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products; these pregnancies occurred while these patients were taking isotretinoin. These reports are more frequent for female patients who use only a single method of contraception. Therefore, it is critically important that females of reproductive potential (FRP) use two effective methods of contraception simultaneously. Patients must receive written warnings about the rates of possible contraception failure (included in patient education kits).

    Using two methods of contraception simultaneously substantially reduces the chances that a female will become pregnant over the risk of pregnancy with either method alone. A drug interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for isotretinoin (see ). Although hormonal contraceptives are highly effective, prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.

    Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John’s Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort.

    If a pregnancy does occur during isotretinoin treatment, isotretinoin must be discontinued immediately. The patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or one month after isotretinoin therapy must be reported immediately to the FDA via the MedWatch number 1-800-FDA-1088 and also the iPLEDGE Pregnancy Registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).

    All Patients

    Isotretinoin is contraindicated in female patients who are pregnant. To receive isotretinoin all patients must meet all of the following conditions:

    Females of Reproductive

    Potential (FRP)

    Isotretinoin is contraindicated in female patients who are pregnant. In addition to the requirements for all patients described above, females of reproductive potential (FRP) must meet the following conditions:

    Pharmacists

    To dispense isotretinoin, pharmacies must be registered and activated with the pregnancy risk management program iPLEDGE.

    The Responsible Site Pharmacist must register the pharmacy by signing and returning the completed registration form. After registration, the Responsible Site Pharmacist can only activate the pharmacy registration by affirming that they meet requirements and will comply with all iPLEDGE requirements by attesting to the following points:

    To dispense isotretinoin, the pharmacist must:

    Isotretinoin capsules must only be dispensed:

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

    Isotretinoin capsules must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE Program. Only FDA-approved isotretinoin products must be distributed, prescribed, dispensed and used. Patients must obtain isotretinoin prescriptions only at US licensed pharmacies.

    A description of the iPLEDGE Program educational materials available with iPLEDGE is provided below. The main goal of these educational materials is to explain the iPLEDGE Program requirements and to reinforce the educational messages.

    Clinical Trials and Postmarketing Surveillance

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

    Body as a Whole

    Allergic reactions, including vasculitis, systemic hypersensitivity (see ), edema, fatigue, lymphadenopathy, weight loss.

    Cardiovascular

    Palpitation, tachycardia, vascular thrombotic disease, stroke.

    Endocrine/Metabolic

    Hypertriglyceridemia (see ), alterations in blood sugar levels (see ).

    Gastrointestinal

    Inflammatory bowel disease (see ), hepatitis (see ), pancreatitis (see ), bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms.

    Hematologic

    Allergic reactions (see ), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see ). See for other hematological parameters.

    Musculoskeletal

    Skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases in bone mineral density (see ), musculoskeletal symptoms (sometimes severe) including back pain, myalgia and arthralgia (see ), transient pain in the chest (see ), arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see ).

    Neurological

    Pseudotumor cerebri (see ), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness.

    Psychiatric

    Suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see ), emotional instability. Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.

    Reproductive System

    Abnormal menses.

    Respiratory

    Bronchospasms (with or without a history of asthma), respiratory infection, voice alteration.

    Skin and Appendages

    Acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas, 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 ), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see ).

    Special Senses:

    Hearing:

    Vision:

    Urinary System:

    Laboratory

    Elevation of plasma triglycerides (see ), 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 ).

    Elevation of fasting blood sugar, elevations of CPK (see ), hyperuricemia.

    Decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis; (see ), elevated sedimentation rates, elevated platelet counts, thrombocytopenia.

    White cells in the urine, proteinuria, microscopic or gross hematuria.

    &times

    Reference

    This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
    "https://dailymed.nlm.nih.gov/dailymed/"

    While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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    Professional

    Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72
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    Interactions

    Interactions

    A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).