Isotretinoin (Page 4 of 9)

6 ADVERSE REACTIONS

The following adverse reactions with isotretinoin or other isotretinoin capsule products are described in more detail in other sections of the labeling:

  • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)]
  • Psychiatric Disorders [see Warnings and Precautions (5.4)]
  • Intracranial Hypertension (Pseudotumor Cerebri) [see Warnings and Precautions (5.5)]
  • Serious Skin Reactions [see Warnings and Precautions (5.6)]
  • Pancreatitis [see Warnings and Precautions (5.7)]
  • Lipid Abnormalities [see Warnings and Precautions (5.8)]
  • Hearing Impairment [see Warnings and Precautions (5.9)]
  • Hepatotoxicity [see Warnings and Precautions (5.10)]
  • Inflammatory Bowel Disease [see Warnings and Precautions (5.11)]
  • Musculoskeletal Abnormalities [see Warnings and Precautions (5.12)]
  • Ocular Abnormalities [see Warnings and Precautions (5.13)]
  • Hypersensitivity Reactions [see Warnings and Precautions (5.14)]

The following adverse reactions associated with the use of isotretinoin capsules were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Dose Relationship

Cheilitis and hypertriglyceridemia were dose related.

Body as a Whole

Fatigue, irritability, pain, allergic reactions, systemic hypersensitivity, edema, lymphadenopathy, weight loss.

Cardiovascular

Vascular thrombotic disease, stroke, palpitation, tachycardia.

Endocrine/Metabolism and Nutritional

Decreased appetite, weight fluctuation, alterations in blood sugar.

Gastrointestinal

Dry lips, chapped lips, cheilitis, nausea, constipation, diarrhea, abdominal pain, vomiting, inflammatory bowel disease, hepatitis, pancreatitis, bleeding and inflammation of the gums, colitis, esophagitis, esophageal ulceration, ileitis.

Hematologic

Anemia and decreased RBC parameters, thrombocytopenia, increased platelet counts, decreased WBC counts, severe neutropenia, rare reports of agranulocytosis.

Infections and Infestations

Nasopharyngitis, hordeolum, infections (including disseminated herpes simplex and upper respiratory tract infection).

Laboratory Abnormalities

The following lab tests were increased: creatine phosphokinase (CPK), triglycerides, alanine aminotransferase (SGPT), aspartate aminotransferase (SGOT), gamma-glutamyltransferase (GGTP), cholesterol, low density lipoprotein (LDL), alkaline phosphatase, bilirubin, LDH, fasting blood glucose, uric acid, and sedimentation rate. However, high density lipoprotein (HDL) was decreased. Urine findings included increased white cells, proteinuria, microscopic or gross hematuria.

Musculoskeletal and Connective Tissue

Decreases in bone mineral density, musculoskeletal symptoms (sometimes severe) including back pain, arthralgia, musculoskeletal pain, neck pain, extremity pain, myalgia, musculoskeletal stiffness [see Warnings and Precautions (5.12)] , skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, tendonitis, arthritis, transient chest pain, and rare reports of rhabdomyolysis.

Neurological

Headache, syncope, intracranial hypertension (pseudotumor cerebri), dizziness, drowsiness, lethargy, malaise, nervousness, paresthesia, seizures, stroke, weakness.

Psychiatric

Suicidal ideation, insomnia, anxiety, depression, irritability, panic attack, anger, euphoria, violent behaviors, emotional instability, suicide attempts, suicide, aggression, psychosis and auditory hallucinations. 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, sexual dysfunction, including erectile dysfunction and decreased libido.

Respiratory

Epistaxis, nasal dryness, bronchospasm (with or without a history of asthma), respiratory infection, voice alteration.

Skin and Subcutaneous Tissue

Dry skin, dermatitis, eczema, rash, contact dermatitis, alopecia, pruritus, sunburn, erythema, acne fulminans, alopecia (which in some cases persisted), bruising, dry nose, eruptive xanthomas, erythema multiforme, flushing, skin fragility, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, nail dystrophy, paronychia, peeling of palms and soles, photoallergic/photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson syndrome, increased sunburn susceptibility, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including granulomatosis with polyangiitis), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting).

Senses

Hearing: tinnitus and hearing impairment.

Ocular: dry eyes, reduced visual acuity, blurred vision, eye pruritis, eye irritation, asthenopia, decreased night vision, ocular hyperemia, increased lacrimation, conjunctivitis, corneal opacities, decreased night vision which may persist, cataracts, color vision disorder, conjunctivitis, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances.

Renal and Urinary

Glomerulonephritis.

7 DRUG INTERACTIONS

7.1 Vitamin A

Isotretinoin is closely related to vitamin A. Therefore, the use of both vitamin A and isotretinoin at the same time may lead to vitamin A related adverse reactions. Patients treated with isotretinoin should be advised against taking supplements containing Vitamin A to avoid additive toxic effects.

7.2 Tetracyclines

Concomitant treatment with isotretinoin and tetracyclines should be avoided because isotretinoin use has been associated with a number of cases of intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines [see Warnings and Precautions (5.5)].

7.3 Phenytoin

Phenytoin is known to cause osteomalacia. No formal clinical trials have been conducted to assess if there is an interactive effect on bone loss between phenytoin and isotretinoin. Therefore, caution should be exercised when using these drugs together.

7.4 Systemic Corticosteroids

Systemic corticosteroids are known to cause osteoporosis. No formal clinical trials have been conducted to assess if there is an interactive effect on bone loss with concomitant use of systemic corticosteroids and isotretinoin. Therefore, caution should be exercised when using these drugs together.

7.5 Norethindrone and Ethinyl Estradiol

In a trial of 31 premenopausal female patients with severe recalcitrant nodular acne receiving norethindrone and ethinyl estradiol as an oral contraceptive agent, isotretinoin capsules within the recommended dosage, did not induce clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Although this study did not show any clinically significant interaction between isotretinoin and norethindrone, it is not known if there is an interaction between isotretinoin with other progestins.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to isotretinoin during pregnancy. Report any suspected fetal exposure during or 1 month after isotretinoin therapy immediately to the FDA via the MedWatch telephone number 1-800-FDA-1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).

Risk Summary

Isotretinoin is contraindicated during pregnancy because isotretinoin can cause fetal harm when administered to a pregnant patient. There is an increased risk of major congenital malformations, spontaneous abortions, and premature births following isotretinoin exposure during pregnancy in humans. If isotretinoin is used during pregnancy, or if the patient becomes pregnant while taking isotretinoin, the patient should be apprised of the potential hazard to a fetus. If pregnancy occurs during treatment of a patient who is taking isotretinoin, isotretinoin must be discontinued immediately and the patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Data

Human Data

Major congenital malformations that have been documented following isotretinoin exposure include malformations of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. External malformations include: skull; ear (including anotia, micropinna, small or absent external auditory canals); eye (including microphthalmia); facial dysmorphia and cleft palate. Internal abnormalities include: CNS (including cerebral and cerebellar malformations, hydrocephalus, microcephaly, cranial nerve deficit); cardiovascular; thymus gland; parathyroid hormone deficiency. In some cases, death has occurred as a result of the malformations.

Cases of IQ scores less than 85 with or without other abnormalities have been reported in children exposed in utero to isotretinoin. An increased risk of spontaneous abortion and premature births have been reported with isotretinoin exposure during pregnancy.

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