Aknenormin

Overdose

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.

ABSORICA causes serious birth defects at any dosage (see BOXED

The oral LD50 of isotretinoin is greater than 4000 mg/kg in rats and mice ( > 600 times the recommended clinical dose of 1.0 mg/kg/day after normalization of the rat dose for total body surface area and > 300 times the recommended clinical dose of 1.0 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 1.0 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.

Aknenormin (isotretinoin) causes serious birth defects at any dosage (see Boxed

Isotretinoin is a derivative of vitamin A. Although the acute toxicity of isotretinoin is low, signs of hypervitaminosis A could appear in cases of accidental overdose. Manifestations of acute vitamin A toxicity include severe headache, nausea or vomiting, drowsiness, irritability and pruritus. Signs and symptoms of accidental or deliberate overdosage with isotretinoin would probably be similar. These symptoms would be expected to be reversible and to subside without the need for treatment.

Aknenormin is a derivative of vitamin A. Although the acute toxicity of Aknenormin is low, signs of hypervitaminosis A could appear in cases of accidental overdose. Manifestations of acute vitamin A toxicity include severe headache, nausea or vomiting, drowsiness, irritability and pruritus. Signs and symptoms of accidental or deliberate overdosage with Aknenormin would probably be similar. These symptoms would be expected to be reversible and to subside without the need for treatment.

Symptoms and signs

Oral ingestion of a 30g tube of topical isotretinoin would result in less exposure than achieved with the recommended dosage of oral isotretinoin. Consequently, the theoretical occurrence of symptoms of overdosage (e.g. hypervitaminosis A) is highly unlikely.

The gel formulation contains more than 95% ethanol. Systemic absorption of this should be considered in the event of oral ingestion.

Treatment

Further management should be as clinically indicated or as recommended by the national poisons centre, where available.

Contraindications

ABSORICA can cause fetal harm when administered to a pregnant woman. Major congenital malformations, spontaneous abortions, and premature births have been documented following pregnancy exposure to isotretinoin in any amount and even for short periods of time. ABSORICA is contraindicated in females who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, treatment should be discontinued and the patient should be apprised of the potential hazard to the fetus.

Hypersensitivity to this product (or Vitamin A, given the chemical similarity to isotretinoin) or to any of its components.

Category X. See Boxed CONTRAINDICATIONS AND WARNINGS.

Aknenormin (isotretinoin) is contraindicated in patients who are hypersensitive to this medication or to any of its components. Aknenormin (isotretinoin) should not be given to patients who are sensitive to parabens, which are used as preservatives in the gelatin capsule (see PRECAUTIONS: Hypersensitivity).

Isotretinoin is contraindicated in women who are pregnant or breastfeeding.

Isotretinoin is contraindicated in women of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme are met.

Isotretinoin is also contraindicated in patients

- With hepatic insufficiency

- With excessively elevated blood lipid values

- With hypervitaminosis A

- Receiving concomitant treatment with tetracyclines.

Aknenormin is contraindicated in women who are pregnant or breast-feeding.

Aknenormin is contraindicated in women of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme are met.

Aknenormin is also contraindicated in patients

With hepatic insufficiency

With excessively elevated blood lipid values

With hypervitaminosis A

With hypersensitivity to Aknenormin or to any of the excipients

Receiving concomitant treatment with tetracyclines

Allergic to peanut or soya oil as Aknenormin contains soya-bean oil

Aknenormin Gel is contraindicated in pregnancy and lactation.

Incompatibilities

Not applicable.

Undesirable effects

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

• Embryofetal Toxicity
• Psychiatric Disorders
• Pseudotumor Cerebri
• Serious Skin Reactions
• Pancreatitis
• Lipid Abnormalities
• Hearing Impairment
• Hepatotoxicity
• Inflammatory Bowel Disease
• Skeletal Abnormalities
• Ocular Abnormalities
• Hypersensitivity

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of ABSORICA cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice.

The adverse reactions listed below reflect both clinical experience with ABSORICA, and consider other adverse reactions that are known from clinical trials and the post-marketing surveillance with oral isotretinoin. The relationship of some of these events to isotretinoin therapy is unknown. Many of the side effects and adverse events 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).

Cheilitis and hypertriglyceridemia are adverse reactions that are usually dose related. Most adverse reactions reported in clinical trials with isotretinoin were reversible when therapy was discontinued; however, some persisted after cessation of therapy.

The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): fatigue, irritability, pain. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: allergic reactions, including vasculitis, systemic hypersensitivity, edema, lymphadenopathy, weight loss.

The following adverse reactions have been reported with isotretinoin: vascular thrombotic disease, stroke, palpitation, tachycardia.

The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): decreased appetite, weight fluctuation, hyperlipidaemia. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: hypertriglyceridemia, alterations in blood sugar.

The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): lip dry, chapped lips, cheilitis, nausea, constipation, diarrhea, abdominal pain, vomiting. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: inflammatory bowel disease, hepatitis, pancreatitis, bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, and other nonspecific gastrointestinal symptoms.

The following adverse reactions have been reported with isotretinoin: allergic reactions, anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis.

The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): nasopharyngitis, hordeolum, upper respiratory tract infection. In addition to the above adverse reactions, the following adverse reaction has been reported with isotretinoin: infections (including disseminated herpes simplex).

The following changes in laboratory tests have been noted in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): blood creatine phosphokinase (CPK) increased, blood triglycerides increased, alanine aminotransferase (SGPT) increased, aspartate aminotransferase (SGOT) increased, gamma-glutamyltransferase (GGTP) increased, blood cholesterol increased, low density lipoprotein (LDL) increased, white blood cell count decreased, blood alkaline phosphatase increased, blood bilirubin increased, blood glucose increased, high density lipopoprotein (HDL) decreased, bone mineral density decreased. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: increased LDH, elevation of fasting blood sugar, hyperuricemia, decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis), elevated sedimentation rates, elevated platelet counts, thrombocytopenia, white cells in the urine, proteinuria, microscopic or gross hematuria.

The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): decreases in bone mineral density, musculoskeletal symptoms (sometimes severe) including back pain, athralgia, musculoskeletal discomfort, musculoskeletal pain, neck pain, pain in extremity, myalgia, musculoskeletal stiffness. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, tendonitis, arthritis, transient pain in the chest, and rare reports of rhabdomyolysis.

The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): headache, syncope. In addition to the above adverse reactions, other adverse reactions reported with isotretinoin include: pseudotumor cerebri, dizziness, drowsiness, lethargy, malaise, nervousness, paresthesias, seizures, stroke, weakness.

The following adverse reactions have been reported in clinical trials conducted with ABSORICA and a generic product of Accutane® (isotretinoin): suicidal ideation, insomnia, anxiety, depression, irritability, panic attack, anger, euphoria, violent behaviors, emotional instability. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: suicide attempts, suicide, aggression, psychosis and hallucination auditory. Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.

The following adverse reaction has been reported with isotretinoin: abnormal menses.

The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): epistaxis, nasal dryness. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: bronchospasms (with or without a history of asthma), respiratory infection, voice alteration.

The following adverse reactions have been reported in a clinical trial conducted with ABSORICA and a generic product of Accutane® (isotretinoin): dry skin, dermatitis, eczema, rash, dermatitis contact, alopecia, pruritus, sunburn, erythema. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: acne fulminans, alopecia (which in some cases persists), bruising, dry nose, eruptive xanthomas, erythema multiforme, flushing, fragility of skin, 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, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including Wegener's granulomatosis), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting).

Hearing: The following adverse reactions have been reported with isotretinoin: tinnitus and hearing impairment.

Ocular: The following adverse reactions have been reported in clinical trials conducted with ABSORICA and a generic product of Accutane® (isotretinoin): dry eye, visual acuity reduced, vision blurred, eye pruritis, eye irritation, asthenopia, decreased night vision, ocular hyperemia, increased lacrimation, and conjunctivitis. In addition to the above adverse reactions, the following adverse reactions have been reported with isotretinoin: corneal opacities, decreased night vision which may persist, cataracts, color vision disorder, conjunctivitis, eyelid inflammation, keratitis, optic neuritis, photobia, visual disturbances.

The following adverse reactions have been reported in clinical trials conducted with isotretinoin: glomerulonephritis, nonspecific urogenital findings.

The adverse reactions listed below reflect the experience from investigational studies of Aknenormin (isotretinoin) , and the postmarketing experience. The relationship of some of these events to Aknenormin (isotretinoin) therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving Aknenormin (isotretinoin) are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, eg, of the lips, nasal passage, and eyes).

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 WARNINGS and ADVERSE REACTIONS).

allergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS: Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss

palpitation, tachycardia, vascular thrombotic disease, stroke

hypertriglyceridemia (see WARNINGS: Lipids), alterations in blood sugar levels (see PRECAUTIONS: Laboratory Tests)

inflammatory bowel disease (see WARNINGS: Inflammatory Bowel Disease), hepatitis (see WARNINGS: Hepatotoxicity), pancreatitis (see WARNINGS: Lipids), bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms

allergic reactions (see PRECAUTIONS: Hypersensitivity), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see PATIENT INFORMATION). See PRECAUTIONS: Laboratory Tests for other hematological parameters.

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

pseudotumor cerebri (see WARNINGS: Pseudotumor Cerebri), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness

suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see WARNINGS: Psychiatric Disorders), emotional instability

Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.

abnormal menses

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

acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas,7 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 PRECAUTIONS: Hypersensitivity), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see PATIENT INFORMATION)

Hearing - hearing impairment (see WARNINGS: Hearing Impairment), tinnitus.

Vision- corneal opacities (see WARNINGS: Corneal Opacities), decreased night vision which may persist (see WARNINGS: Decreased Night Vision), cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances

glomerulonephritis (see PRECAUTIONS: Hypersensitivity), nonspecific urogenital findings (see PRECAUTIONS: Laboratory Tests for other urological parameters)

Elevation of plasma triglycerides (see WARNINGS: Lipids), 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 WARNINGS: Hepatotoxicity)

Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS: Laboratory Tests), hyperuricemia

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

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

Summary of safety profile

Some of the side effects associated with the use of isotretinoin are dose-related. The side effects are generally reversible after altering the dose or discontinuation of treatment, however some may persist after treatment has stopped. The following symptoms are the most commonly reported undesirable effects with isotretinoin: dryness of the skin, dryness of the mucosae e.g. of the lips (cheilitis), the nasal mucosa (epistaxis) and the eyes (conjunctivitis).

Tabulated list of adverse reactions

The incidence of the adverse reactions calculated from pooled clinical trial data involving 824 patients and from post-marketing data are presented in the table below. The adverse reactions are listed below by MedDRA system organ class (SOC) and categories of frequency. Frequency categories are defined as Very common (>1/10), Common (>1/100 to <1/10), Uncommon (>1/1,000 to <1/100), Rare (>1/10,000 to <1/1,000), Very rare (>1/10,000 to <1/1,000) and not known (cannot be estimated from the available data). Within each frequency grouping and SOC, adverse reactions are presented in order of decreasing seriousness.

Table 1 Tabulated list of adverse reactions in patients treated with isotretinoin

* cannot be estimated from the available data

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Summary of safety profile

Some of the side effects associated with the use of Aknenormin are dose-related. The side effects are generally reversible after altering the dose or discontinuation of treatment, however some may persist after treatment has stopped. The following symptoms are the most commonly reported undesirable effects with Aknenormin: dryness of the mucosae e.g. of the lips (cheilitis), the nasal mucosa (epistaxis), and the eyes (conjunctivitis), dryness of the skin.

Tabulated list of adverse reactions

The incidence of the adverse reactions calculated from pooled clinical trial data involving 824 patients and from postmarketing data are presented in the table below. The adverse reactions are listed below by MedDRA system organ class (SOC) and categories of frequency. Frequency categories are defined as very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (>1/10,000 to <1/1,000) and not known (cannot be estimated from the available data). Within each frequency grouping and SOC, adverse reactions are presented in order of decreasing seriousness.

Table 1 Tabulated list of adverse reactions in patients treated with Aknenormin

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

The frequency of adverse reactions listed below is defined using the following convention: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Skin and subcutaneous tissue disorders

Post-marketing data:

The following adverse drug reactions are based on post-marketing reports. Since these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency, however in reality the following reactions are rarely seen.

Skin and subcutaneous tissue disorders

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Preclinical safety data

Acute toxicity

The acute oral toxicity of isotretinoin was determined in various animal species. LD50 is approximately 2000 mg/kg in rabbits, approximately 3000 mg/kg in mice, and over 4000 mg/kg in rats.

Chronic toxicity

A long-term study in rats over 2 years (isotretinoin dosage 2, 8 and 32 mg/kg/d) produced evidence of partial hair loss and elevated plasma triglycerides in the higher dose groups. The side effect spectrum of isotretinoin in the rodent thus closely resembles that of vitamin A, but does not include the massive tissue and organ calcifications observed with vitamin A in the rat. The liver cell changes observed with vitamin A did not occur with isotretinoin.

All observed side effects of hypervitaminosis A syndrome were spontaneously reversible after withdrawal of isotretinoin. Even experimental animals in a poor general state had largely recovered within 1-2 weeks.

Teratogenicity

Like other vitamin A derivatives, isotretinoin has been shown in animal experiments to be teratogenic and embryotoxic.

Mutagenicity

Isotretinoin has not been shown to be mutagenic in in vitro or in vivo animal tests.

Acute toxicity

The acute oral toxicity of Aknenormin was determined in various animal species. LD50 is approximately 2000 mg/kg in rabbits, approximately 3000 mg/kg in mice, and over 4000 mg/kg in rats.

Chronic toxicity

A long-term study in rats over 2 years (Aknenormin dosage 2, 8 and 32 mg/kg/d) produced evidence of partial hair loss and elevated plasma triglycerides in the higher dose groups. The side effect spectrum of Aknenormin in the rodent thus closely resembles that of vitamin A, but does not include the massive tissue and organ calcifications observed with vitamin A in the rat. The liver cell changes observed with vitamin A did not occur with Aknenormin.

All observed side effects of hypervitaminosis A syndrome were spontaneously reversible after withdrawal of Aknenormin. Even experimental animals in a poor general state had largely recovered within 1-2 weeks.

Teratogenicity

Like other vitamin A derivatives, Aknenormin has been shown in animal experiments to be teratogenic and embryotoxic.

Mutagenicity

Aknenormin has not been shown to be mutagenic nor carcinogenic in in vitro or in vivo animal tests respectively.

Carcinogenesis/Mutagenesis

In a carcinogenicity study in Fischer 344 rats given oral isotretinoin up to 32 mg/kg/day, there was an increased incidence of phaeochromocytomas relative to controls in both sexes at 32 mg/kg/day and in males at 8 mg/kg/day. Given the high rate of spontaneous rate of occurrence of phaeochromoyctoma in Fischer 344 rats, the relevance of this tumour to humans is uncertain.

Studies in hairless mice suggest that concurrent dermal exposure to isotretinoin at dose levels up to 500 mg/kg may enhance the tumorigenic potential of UV irradiation. The significance of these studies to humans is not clear.

The mutagenic potential of isotretinoin was evaluated in the Ames assay with and without S9 metabolic activation and in the Chinese hamster lung cell for chromosome aberrations, both of which were negative.

Reproductive Toxicology

Fertility

In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dose levels of isotretinoin up to 32 mg/kg/day.

In dogs, testicular atrophy was noted after approximately 30 weeks at isotretinoin dose levels of 20 or 60 mg/kg/day. However, in studies of men receiving oral isotretinoin, no significant effects have been seen on semen parameters.

Pregnancy

Reproduction studies conducted in rabbits using isotretinoin gel applied topically at up to 60 times the human dose have revealed no harm to the foetus.

Topical application of high doses of tretinoin (an isomer of isotretinoin) induces maternal toxicity, which limits the maximum dose to a level potentially below that associated with embryofoetal alterations by other routes of administration.

In one study, topical doses of a 0.1% ethanol solution, given to Wistar rats through gestational days (GDs) 6 to 16, were not tolerated at 10 mg/kg/day, causing severe local and systemic maternal toxicity. Offspring of dams receiving 5 mg/kg weighed significantly less than those of controls. Maternal toxicity (reduced weight gain and food consumption) was also evident at doses of 2.5 mg/kg/day or more. A significant increase in the occurrence of supernumerary ribs was observed at this dose, a result thought to be nonspecific or maternally mediated.

Topical administration of tretinoin at a dose of 10.5 mg/kg/day for 3 days to intact skin of hamsters on GDs 7, 8, and 9 resulted in erythema and/or epidermal hyperplasia at the site of application, but did not cause a significant teratogenic response.

Topical administration of 5 g 0.05% tretinoin ointment (corresponding to a dose of ~ 10 mg/kg) to the shaved backs of pregnant rats on GD 12 resulted in some retinoid-specific patterns of anomalies (humerus short 9%, radius bent 6%, ribs wavy 80%). This dose was ~100 fold that expected in humans.

Pharmacotherapeutic group

Pharmacodynamic properties

The pharmacodynamics of ABSORICA are unknown.

Pharmacotherapeutic group: Retinoid for treatment of acne.

ATC code: D10B A01

Mechanism of action

Isotretinoin is a stereoisomer of all-trans retinoic acid (tretinoin). The exact mechanism of action of isotretinoin has not yet been elucidated in detail, but it has been established that the improvement observed in the clinical picture of severe acne is associated with suppression of sebaceous gland activity and a histologically demonstrated reduction in the size of the sebaceous glands. Furthermore, a dermal anti-inflammatory effect of isotretinoin has been established.

Clinical efficacy and safety

Hypercornification of the epithelial lining of the pilosebaceous unit leads to shedding of corneocytes into the duct and blockage by keratin and excess sebum. This is followed by formation of a comedone and, eventually, inflammatory lesions. Isotretinoin inhibits proliferation of sebocytes and appears to act in acne by re-setting the orderly program of differentiation. Sebum is a major substrate for the growth of Propionibacterium acnes so that reduced sebum production inhibits bacterial colonisation of the duct.

Pharmacotherapeutic group: Retinoid for the treatment of acne, ATC code: D10BA01

Mechanism of action

Aknenormin is a stereoisomer of all-trans retinoic acid (tretinoin). The exact mechanism of action of Aknenormin has not yet been elucidated in detail, but it has been established that the improvement observed in the clinical picture of severe acne is associated with suppression of sebaceous gland activity and a histologically demonstrated reduction in the size of the sebaceous glands. Furthermore, a dermal anti-inflammatory effect of Aknenormin has been established.

Clinical efficacy and safety

Hypercornification of the epithelial lining of the pilosebaceous unit leads to shedding of corneocytes into the duct and blockage by keratin and excess sebum. This is followed by formation of a comedone and, eventually, inflammatory lesions. Aknenormin inhibits proliferation of sebocytes and appears to act in acne by re-setting the orderly programme of differentiation. Sebum is a major substrate for the growth of Propionibacterium acnes so that reduced sebum production inhibits bacterial colonisation of the duct.

Pharmacotherapeutic group: retinoids for topical use in acne, isotretinoin.

ATC Code: D10A D04

Mechanism of action

Isotretinoin is structurally and pharmacologically related to vitamin A which regulates epithelial cell growth and differentiation. It is thought that topically applied isotretinoin acts in a comparable way to its stereoisomer, tretinoin, and:

- stimulates mitosis in the epidermis

- reduces intercelluar cohesion in the stratum corneum

- contests the hyperkeratosis characteristic of acne vulgaris

- aids desquamation, preventing the formation of lesions

- mediates an increased production of less cohesive epidermal sebaceous cells, which appears to promote the initial expulsion of comedones and their subsequent prevention.

Isotretinoin has topical anti-inflammatory actions. Topically applied isotretinoin inhibits leukotriene-B4-induced migration of polymorphonuclear leukocytes, which accounts for topical isotretinoin's anti-inflammatory action. A significant inhibition was produced by topically applied isotretinoin but only a weak inhibition by topical tretinoin. This may account for the reduced rebound effect seen with topical isotretinoin when compared with topical tretinoin.

Pharmacodynamic effects

The pharmacological action of isotretinoin remains to be fully elucidated.

Isotretinoin binds to the 3 retinoic acid receptors (RAR) alpha, beta and gamma with less affinity and is unable to bind to retinoid X receptors (RXR) and the retinoic acid cellular receptor (CRABP).

There are studies which show similar activity to systemic actions when administered topically. Inhibition of sebum production by topical isotretinoin has been demonstrated in the ears and flank organs of the Syrian hamster. Application of isotretinoin to the ear for 15 days led to a 50% reduction in sebaceous gland size, and application to the flank organ resulted in a 40% reduction. Topical application of isotretinoin has also been shown to have an effect on the epidermal differentiation of rhino mouse skin. Reduction in the size of the utriculi or superficial cysts leading to normal looking follicles was a predominant feature of isotretinoin treatment and has been used to quantify the antikeratinising effects of isotretinoin.

Pharmacokinetic properties

Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high-fat meal. ABSORICA is bioequivalent to Accutane® (isotretinoin) capsule when both drugs are taken with a high-fat meal. ABSORICA is more bioavailable than Accutane® (isotretinoin) capsules when both drugs are taken fasted; the AUC0-t of ABSORICA is approximately 83% greater than that of Accutane®. ABSORICA is therefore not interchangeable with generic products of Accutane®.

A single dose two-way crossover pharmacokinetic trial was conducted in 14 healthy adult male subjects comparing ABSORICA 40 mg (1 x 40 mg capsules), dosed under fasted and fed conditions. Under fed conditions after a high-fat meal, it was observed that the mean AUC0-t and Cmax were approximately 50% and 26% higher, than that observed under fasting conditions (Table 2). The observed elimination half-life (T½) was slightly lower in the fed state versus fasted. The time to peak concentration (Tmax) increased with food and this may be related to a longer absorption phase.

Table 2: Pharmacokinetic parameters of ABSORICA mean (%CV) following administration of 40 mg strength, N=14

Published clinical literature has shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin.

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

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 40 mg oral dose of ABSORICA to 57 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.

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.

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 40 mg (2 x 20 mg) oral dose of ABSORICA to 57 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (T½) of isotretinoin and 4-oxo-isotretinoin under fed states were 18 hours and 38 hours, respectively.

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. There were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and adult patients.

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

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-oxotretinoin). 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 Aknenormin (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.

Following oral administration of an 80 mg dose of 14C-isotretinoin as a liquid suspension, 14Cactivity 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 Aknenormin (isotretinoin) to 74 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (t½) of isotretinoin and 4-oxo-isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.90 to 5.43 in patients with cystic acne.

Absorption

The absorption of isotretinoin from the gastro-intestinal tract is variable and dose-linear over the therapeutic range. The absolute bioavailability of isotretinoin has not been determined, since the compound is not available as an intravenous preparation for human use, but extrapolation from dog studies would suggest a fairly low and variable systemic bioavailability. When isotretinoin is taken with food, the bioavailability is doubled relative to fasting conditions.

Distribution

Isotretinoin is extensively bound to plasma proteins, mainly albumin (99.9 %). The volume of distribution of isotretinoin in man has not been determined since isotretinoin is not available as an intravenous preparation for human use. In humans little information is available on the distribution of isotretinoin into tissue. Concentrations of isotretinoin in the epidermis are only half of those in serum. Plasma concentrations of isotretinoin are about 1.7 times those of whole blood due to poor penetration of isotretinoin into red blood cells.

Biotransformation

After oral administration of isotretinoin, three major metabolites have been identified in plasma: 4-oxo-isotretinoin, tretinoin, (all-trans retinoic acid), and 4-oxo-tretinoin. These metabolites have shown biological activity in several in vitro tests. 4-oxo-isotretinoin has been shown in a clinical study to be a significant contributor to the activity of isotretinoin (reduction in sebum excretion rate despite no effect on plasma levels of isotretinoin and tretinoin). Other minor metabolites includes glucuronide conjugates. The major metabolite is 4-oxo-isotretinoin with plasma concentrations at steady state, that are 2.5 times higher than those of the parent compound.

Isotretinoin and tretinoin (all-trans retinoic acid) are reversibly metabolised (interconverted), and the metabolism of tretinoin is therefore linked with that of isotretinoin. It has been estimated that 20-30 % of an isotretinoin dose is metabolised by isomerisation.

Enterohepatic circulation may play a significant role in the pharmacokinetics of isotretinoin in man. In vitro metabolism studies have demonstrated that several CYP enzymes are involved in the metabolism of isotretinoin to 4-oxo-isotretinoin and tretinoin. No single isoform appears to have a predominant role. Isotretinoin and its metabolites do not significantly affect CYP activity.

Elimination

After oral administration of radiolabelled isotretinoin approximately equal fractions of the dose were recovered in urine and faeces. Following oral administration of isotretinoin, the terminal elimination half-life of unchanged drug in patients with acne has a mean value of 19 hours. The terminal elimination half-life of 4-oxo-isotretinoin is longer, with a mean value of 29 hours.

Isotretinoin is a physiological retinoid and endogenous retinoid concentrations are reached within approximately two weeks following the end of isotretinoin therapy.

Hepatic impairment

Since isotretinoin is contraindicated in patients with hepatic impairment, limited information on the kinetics of isotretinoin is available in this patient population.

Renal impairment

Renal failure does not significantly reduce the plasma clearance of isotretinoin or 4-oxo-isotretinoin.

Absorption

The absorption of Aknenormin from the gastro-intestinal tract is variable and dose-linear over the therapeutic range. The absolute bioavailability of Aknenormin has not been determined, since the compound is not available as an intravenous preparation for human use, but extrapolation from dog studies would suggest a fairly low and variable systemic bioavailability. When Aknenormin is taken with food, the bioavailability is doubled relative to fasting conditions.

Distribution

Aknenormin is extensively bound to plasma proteins, mainly albumin (99.9%). The volume of distribution of Aknenormin in man has not been determined since Aknenormin is not available as an intravenous preparation for human use. In humans little information is available on the distribution of Aknenormin into tissue. Concentrations of Aknenormin in the epidermis are only half of those in serum. Plasma concentrations of Aknenormin are about 1.7 times those of whole blood due to poor penetration of Aknenormin into red blood cells.

Biotransformation

After oral administration of Aknenormin, three major metabolites have been identified in plasma: 4-oxo-Aknenormin, tretinoin (all-trans retinoic acid), and 4-oxo-tretinoin. These metabolites have shown biological activity in several in vitro tests. 4-oxo-Aknenormin has been shown in a clinical study to be a significant contributor to the activity of Aknenormin (reduction in sebum excretion rate despite no effect on plasma levels of Aknenormin and tretinoin). Other minor metabolites include glucuronide conjugates. The major metabolite is 4-oxo-Aknenormin with plasma concentrations at steady state, that are 2.5 times higher than those of the parent compound.

Aknenormin and tretinoin (all-trans retinoic acid) are reversibly metabolised (interconverted), and the metabolism of tretinoin is therefore linked with that of Aknenormin. It has been estimated that 20-30% of an Aknenormin dose is metabolised by isomerisation.

Enterohepatic circulation may play a significant role in the pharmacokinetics of Aknenormin in man. In vitro metabolism studies have demonstrated that several CYP enzymes are involved in the metabolism of Aknenormin to 4-oxo-Aknenormin and tretinoin. No single isoform appears to have a predominant role. Aknenormin and its metabolites do not significantly affect CYP activity.

Elimination

After oral administration of radiolabelled Aknenormin approximately equal fractions of the dose were recovered in urine and faeces. Following oral administration of Aknenormin, the terminal elimination half-life of unchanged drug in patients with acne has a mean value of 19 hours. The terminal elimination half-life of 4-oxo-Aknenormin is longer, with a mean value of 29 hours.

Aknenormin is a physiological retinoid and endogenous retinoid concentrations are reached within approximately two weeks following the end of Aknenormin therapy.

Hepatic impairment

Since Aknenormin is contraindicated in patients with hepatic impairment, limited information on the kinetics of Aknenormin is available in this patient population.

Renal impairment

Renal failure does not significantly reduce the plasma clearance of Aknenormin or 4-oxo-Aknenormin.

Absorption

Following isotretinoin 0.05% gel application to acne patients at a daily dose of 20g (equivalent to 10 mg of isotretinoin) to the face, chest and back for 30 days, plasma concentrations of isotretinoin and tretinoin were not measurable (< 20 ng/mL)

Distribution

Systemic (oral) isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.

Metabolism

In vivo studies in humans showed that the three major metabolites identified in human plasma following systemic (oral) administration of isotretinoin were 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). In vitro studies indicated that all of these metabolites had retinoid activity.

In vitro studies indicate that the major enzymes responsible for isotretinoin metabolism are cytochrome P450 isoenzymes 2C8, 2C9, 3A4 and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates and excreted in urine and faeces.

Elimination

Following systemic (oral) administration of an 80 mg dose of 14C-isotretinoin, radioactivity in the blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately eliminated in the faeces and urine in similar amounts (total of 65% to 83%).

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

ABSORICA must not be used by female patients who are or may become pregnant. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking ABSORICA in any amount, even for short periods of time.

ABSORICA 25 mg contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No.5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

Major congenital malformations, spontaneous abortions, and premature births have been documented following pregnancy exposure to isotretinoin. Females of Reproductive Potential must comply with the pregnancy testing and contraception requirements described in the iPLEDGE program. There are no accurate means of determining whether an exposed fetus has been affected.

Patients must be informed not to donate blood during isotretinoin therapy and for 1 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.

Because of the risk of teratogenicity and to minimize fetal exposure, ABSORICA is available only through a restricted program under a REMS called iPLEDGE. Under the ABSORICA REMS, prescribers, patients, pharmacies, and distributors must enroll and be registered in the program. ABSORICA 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.

Required components of the iPLEDGE Program are:

• ABSORICA must only be prescribed by prescribers who are registered and activated with the iPLEDGE program and agree to comply with the REMS requirements described in the booklets entitled The Guide to Best Practices for the iPLEDGE Program, The iPLEDGE Program Prescriber Contraception Counseling Guide, and Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin.
• Male patients and Females of non-reproductive potential: To obtain ABSORICA, these patients must understand the risks and benefits of ABSORICA, comply with the REMS requirements described in the booklet entitled The iPLEDGE Program Guide to Isotretinoin for Male Patients and Female Patients Who Cannot Get Pregnant, and sign a Patient Information/Informed Consent form.
• Females of reproductive potential: ABSORICA is contraindicated in female patients who are or may become pregnant.
• Females of reproductive potential who are not pregnant must understand the risks and benefits, comply with the REMS requirements described in the booklet entitled The iPLEDGE Program Guide to Isotretinoin for Female Patients Who Can Get Pregnant and The iPLEDGE Program Birth Control Workbook (including the pregnancy testing and contraception requirements ), and sign a Patient Information/Informed Consent form and Patient Information/Informed Consent About Birth Defects form. Additionally, the patient must answer questions about the iPLEDGE program and pregnancy prevention monthly.
• Pharmacies that dispense ABSORICA must be registered and activated with iPLEDGE, must only dispense to patients who are authorized to receive ABSORICA, and agree to comply with the REMS requirements described in the booklet entitled The Pharmacist Guide for the iPLEDGE Program.
• Females of reproductive potential must obtain the prescription within 7 days of the specimen collection for the pregnancy test; male patients and females of non-reproductive potential must obtain the prescription within 30 days of the office visit.
• ABSORICA must only be dispensed in no more than a 30-day supply with a Medication Guide. Refills require a new prescription and a new authorization from the iPLEDGE system.
• Wholesalers and distributors that distribute ABSORICA must be registered with iPLEDGE and agree to comply with the REMS requirements.

If a pregnancy does occur during ABSORICA treatment, ABSORICA 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 1 month after ABSORICA therapy must be reported immediately to the FDA via the MedWatch telephone number 1-800-FDA-1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).

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

Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) are an inadequate method of contraception during ABSORICA therapy.

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 reactions. 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 ABSORICA 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 ABSORICA 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 ABSORICA 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 ABSORICA therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of ABSORICA therapy.

Isotretinoin use has been associated with 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 ABSORICA immediately and be referred to a neurologist for further diagnosis and care.

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

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

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 of 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 the dose while continuing isotretinoin.

Blood lipid determinations should be performed before ABSORICA is given and then at intervals until the lipid response to ABSORICA 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 of triglyceridemia during ABSORICA therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If ABSORICA therapy is instituted, more frequent checks of serum values for lipids and/or blood sugar are recommended.

The cardiovascular consequences of hypertriglyceridemia associated with isotretinoin are unknown.

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 reaction have not been established. Patients who experience tinnitus or hearing impairment should discontinue ABSORICA treatment and be referred for specialized care for further evaluation.

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 with isotretinoin, 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 ABSORICA, the drug should be discontinued and the etiology further investigated.

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 ABSORICA immediately.

Isotretinoin may have a negative effect on bone mineral density (BMD) in some patients. In a clinical trial of ABSORICA and a generic product of Accutane® (isotretinoin), 27/306 (8.8%) of adolescents had BMD declines, defined as ≥ 4% lumbar spine or total hip, or ≥ 5% femoral neck, during the 20 week treatment period. Repeat scans conducted within 2-3 months after the post-treatment scan showed no recovery of BMD. Longer term data at 4-11 months showed that 3 out of 7 patients had total hip and femoral neck BMD below pre-treatment baseline, and 2 others did not show the increase in BMD above baseline expected in this adolescent population. Therefore, physicians should use caution when prescribing ABSORICA to patients with 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.

Approximately 16% of patients treated with isotretinoin 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.

In a trial of pediatric patients treated with isotretinoin, approximately 29% (104/358) 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 ABSORICA. Consideration should be given to discontinuation of ABSORICA if any significant abnormality is found.

There have been spontaneous reports of osteoporosis, osteopenia, bone fractures and/or delayed healing of bone fractures in patients while on therapy with isotretinoin or following cessation of therapy with isotretinoin. While causality to isotretinoin has not been established, an effect cannot be ruled out.

Patients may be at an increased risk when participating in sports with repetitive impact where the risks of spondylolisthesis with and without pars fractures and hip growth plate injures in early and late adolescence are known.

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.

Longer term effects have not been studied. It is important that ABSORICA be given at the recommended doses for no longer than the recommended duration.

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 of isotretinoin. Additionally, skeletal hyperostosis was noted in 6 of 8 patients in a prospective trial of disorders of keratinization. Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by x-ray in prospective trials 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 trial 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.

There are spontaneous literature 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.

In a 20-week clinical trial that included 289 adolescents on ABSORICA or a generic product of Accutane® (isotretinoin) who had hand radiographs taken to assess bone age, a total of 9 (3.11%) patients had bone age changes that were clinically significant and for which a drug-related effect cannot be excluded.

Visual problems should be carefully monitored. All ABSORICA patients experiencing visual difficulties should discontinue ABSORICA treatment and have an ophthalmological examination.

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.

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.

Dry eye has been reported in subjects during isotretinoin therapy. Patients who wear contact lenses may have trouble wearing them while on ABSORICA treatment and afterwards.

Anaphylactic reactions and other allergic reactions have been reported in isotretinoin-treated patients. 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.

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 ABSORICA is established. The incidence of hypertriglyceridemia is 1 patient in 4 on isotretinoin.

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

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 an isotretinoin clinical trial of 924 patients, marked elevations in CPK ( ≥ 350 U/L) were observed in approximately 24% of patients. In another clinical trial of 217 pediatric patients (12 – 17 years) 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 clinical trial.

See FDA-Approved Patient Labeling (Medication Guide)

Advise the patient that ABSORICA is only available through a restricted program called iPLEDGE.

• As a component of the iPLEDGE program, prescribers must instruct patients to read the Medication Guide, the iPLEDGE program patient educational booklets, and watch the video with the following videos — “Be Prepared, Be Protected” and “Be Aware: The Risk of Pregnancy While on Isotretinoin”. The video includes information about contraception, the most common reasons that contraception fails, and the importance of using 2 forms 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 ABSORICA at any time during pregnancy.
• Male patients and Females of non-reproductive potential must understand the risks and benefits of ABSORICA, comply with the REMS requirements described in the booklet entitled The iPLEDGE Program Guide to Isotretinoin for Male Patients and Female Patients Who Cannot Get Pregnant, and sign a Patient Information/Informed Consent form.
• Females of reproductive potential must be instructed that they must not be pregnant when ABSORICA therapy is initiated or plan to become pregnant while receiving ABSORICA therapy. Additionally, they must use 2 forms of effective contraception simultaneously for 1 month before starting ABSORICA, while taking ABSORICA, and for 1 month after ABSORICA has been stopped, unless they commit to continuous abstinence from heterosexual intercourse. They should also sign a Patient Information/Informed Consent form and Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form prior to beginning ABSORICA therapy. 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 ABSORICA prescription is written. Additionally, a pregnancy test must be completed at the end of the entire course of ABSORICA therapy and 1 month after discontinuation of therapy.
• Advise the patient that isotretinoin is found in the semen of male patients taking isotretinoin, 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 post-marketing 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.
• Advise the patient that ABSORICA is available only from pharmacies that are certified in the iPLEDGE program, and provide them with the telephone number (1-866-495-0654) and website (www.ipledgeprogram.com) for information on how to obtain.
• Advise patients that they may be requested to participate in a survey to evaluate the effectiveness of the iPLEDGE program.
• 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 ABSORICA 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. Inform patients that symptoms of depression 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 treatment 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 ABSORICA 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 ABSORICA therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of ABSORICA 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 have tried to end their own lives, and some 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. There have also been reports of psychotic symptoms, which indicate a loss of contact with reality. Psychotic symptoms include feelings of suspiciousness toward others, strange beliefs, hearing voices or other noises without an obvious source, and seeing unusual objects or people with no explanation. No one knows if isotretinoin caused these behaviors and symptoms or if they would have happened even if the person did not take isotretinoin. If any of these behaviors or symptoms occur, the patient should stop treatment and the patient or family member should contact the prescriber promptly without waiting until the next visit. Some people have had other signs of depression while taking isotretinoin.
• Patients must be informed that they must not share ABSORICA with anyone else because of the risk of birth defects and other serious adverse reactions.
• Patients must be informed not to donate blood during therapy and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to ABSORICA.
• ABSORICA may be taken without regard to meals. To decrease the risk of esophageal irritation, patients should swallow the capsules with a full glass of liquid.
• Patients should be informed that inflammatory bowel disease (including regional ileitis) may occur without a prior history of intestinal disorders. In rare instances, symptoms have been reported to persist after treatment has stopped. Patients should be informed that if they experience abdominal pain, rectal bleeding or severe diarrhea, they should discontinue ABSORICA immediately.
• 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 ABSORICA therapy and for at least 6 months thereafter due to the possibility of scarring.
• Patients should be advised to avoid prolonged exposure to UV rays or sunlight.
• Patients should be informed that they may experience dry eye, corneal opacities, and decreased night vision. Contact lens wearers may experience decreased tolerance to contact lenses during and after therapy.
• Patients should be informed that 16% of patients treated with isotretinoin 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 therapy, but in some cases persisted.
• There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity.
• Pediatric patients and their caregivers should be informed that approximately 17% to 29% of pediatric patients treated with isotretinoin developed back pain. In a clinical trial, back pain was severe in 13.5% 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 treatment. Consideration should be given to discontinuation of isotretinoin if any significant abnormality is found.
• Neutropenia and rare cases of agranulocytosis have been reported in patients treated with isotretinoin. ABSORICA 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 in patients treated with isotretinoin. Treatment with ABSORICA should be discontinued if clinically significant skin reactions occur.
• Adolescent patients who participate in sports with repetitive impact should be informed that isotretinoin use may increase their risk of spondylolisthesis or hip growth plate injuries. 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.

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 S. typhimurium 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, S. cerevisiae D7 assay, in vitr

Aknenormin (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 Aknenormin (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 Aknenormin (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 Aknenormin (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 Aknenormin (isotretinoin) therapy is appropriate in this setting; for some patients the risks may outweigh the benefits of Aknenormin (isotretinoin) therapy.

Aknenormin (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 Aknenormin (isotretinoin) immediately and be referred to a neurologist for further diagnosis and care (see ADVERSE REACTIONS: Neurological).

There have been post-marketing reports of erythema multiforme and severe skin reactions [eg, 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 Aknenormin (isotretinoin) should be considered if warranted.

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

Elevations of serum triglycerides in excess of 800 mg/dL have been reported in patients treated with Aknenormin (isotretinoin). Marked elevations of serum triglycerides were reported in approximately 25% of patients receiving Aknenormin (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 Aknenormin (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 Aknenormin (isotretinoin).5

Blood lipid determinations should be performed before Aknenormin (isotretinoin) is given and then at intervals until the lipid response to Aknenormin (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 Aknenormin (isotretinoin) therapy (patients with diabetes, obesity, increased alcohol intake, lipid metabolism disorder or familial history of lipid metabolism disorder). If Aknenormin (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 Aknenormin (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 1.0 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 1.0 mg/kg/day, respectively, after normalization for total body surface area).

Impaired hearing has been reported in patients taking Aknenormin (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 Aknenormin (isotretinoin) treatment and be referred for specialized care for further evaluation (see ADVERSE REACTIONS: Special Senses).

Clinical hepatitis considered to be possibly or probably related to Aknenormin (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 Aknenormin (isotretinoin) , the drug should be discontinued and the etiology further investigated.

Aknenormin (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 Aknenormin (isotretinoin) treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue Aknenormin immediately (see ADVERSE REACTIONS: Gastrointestinal).

Effects of multiple courses of Aknenormin (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 Aknenormin (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 8 of the patients with decreased bone mineral density for up to 11 months thereafter demonstrated increasing bone density in 5 patients at the lumbar spine, while the other 3 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 5 of 8 patients (62.5%).

In a separate open-label extension study of 10 patients, ages 13-18 years, who started a second course of Aknenormin (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 Aknenormin (isotretinoin) population. While causality to Aknenormin (isotretinoin) has not been established, an effect cannot be ruled out. Longer term effects have not been studied. It is important that Aknenormin (isotretinoin) be given at the recommended doses for no longer than the recommended duration.

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 6 of 8 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 Aknenormin (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 Aknenormin (isotretinoin) given in two divided doses. Hyperostosis may require a longer time frame to appear. The clinical course and significance remain unknown.

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

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

Corneal opacities have occurred in patients receiving Aknenormin (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 Aknenormin (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 has been reported during Aknenormin (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.

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

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

For the purpose of the iPLEDGE program, the term wholesaler refers to wholesaler, distributor, and/or chain pharmacy distributor. To distribute Aknenormin (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:

• Registering prior to distributing isotretinoin and re-registering annually thereafter
• Distributing only FDA approved isotretinoin product
• Only shipping isotretinoin to
  • wholesalers registered in the iPLEDGE program with prior written consent from the manufacturer or
  • pharmacies licensed in the US and registered and activated in the iPLEDGE program
• Notifying the isotretinoin manufacturer (or delegate) of any non-registered and/or nonactivated pharmacy or unregistered wholesaler that attempts to order isotretinoin
• Complying with inspection of wholesaler records for verification of compliance with the iPLEDGE program by the isotretinoin manufacturer (or delegate)
• Returning to the manufacturer (or delegate) any undistributed product if registration is revoked by the manufacturer or if the wholesaler chooses to not re-register annually

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:

• I know the risk and severity of fetal injury/birth defects from isotretinoin.
• I know the risk factors for unplanned pregnancy and the effective measures for avoidance of unplanned pregnancy.
• I have the expertise to provide the patient with detailed pregnancy prevention counseling or I will refer her to an expert for such counseling, reimbursed by the manufacturer.
• I will comply with the iPLEDGE program requirements described in the booklets entitled The Guide to Best Practices for the iPLEDGE Program and The iPLEDGE Program Prescriber Contraception Counseling Guide.
• Before beginning treatment of female patients of childbearing potential with isotretinoin and on a monthly basis, the patient will be counseled to avoid pregnancy by using two forms of contraception simultaneously and continuously one month before, during, and one month after isotretinoin therapy, unless the patient commits to continuous abstinence.
• I will not prescribe isotretinoin to any female patient of childbearing potential until verifying she has a negative screening pregnancy test and monthly negative CLIA-certified (Clinical Laboratory Improvement Amendment) pregnancy tests. Patients should have a pregnancy test at the completion of the entire course of isotretinoin and another pregnancy test 1 month later.
• I will report any pregnancy case that I become aware of while the female patient is on isotretinoin or 1 month after the last dose to the pregnancy registry.

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 female patients of childbearing potential:
   • Enter patient's two chosen forms of contraception each month.
   • Enter monthly result from CLIA-certified laboratory conducted pregnancy test.

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 patient of childbearing potential signifies that she:

• Has been counseled and has signed a Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin. The patient must sign the informed consent form before starting treatment and patient counseling must also be done at that time and on a monthly basis thereafter.
• Has 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 2 tests should be at least 19 days.
  • For patients with regular menstrual cycles, the second pregnancy test should be done during the first 5 days of the menstrual period immediately preceding the beginning of isotretinoin therapy and after the patient has used 2 forms 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 2 forms of contraception for 1 month.
• Has had a negative result from a urine or serum pregnancy test in a CLIA-certified laboratory before receiving each subsequent course of isotretinoin. A pregnancy test must be repeated every month, in a CLIA-certified laboratory, prior to the female patient receiving each prescription.
• Has selected and has committed to use 2 forms of effective contraception simultaneously, at least 1 of which must be a primary form, unless the patient commits to continuous abstinence from heterosexual contact, or the patient has undergone a hysterectomy or bilateral oophorectomy, or has been medically confirmed to be post-menopausal. Patients must use 2 forms of effective contraception for at least 1 month prior to initiation of isotretinoin therapy, during isotretinoin therapy, and for 1 month after discontinuing isotretinoin therapy. Counseling about contraception and behaviors associated with an increased risk of pregnancy must be repeated on a monthly basis.
  If the patient has unprotected heterosexual intercourse at any time 1 month before, during, or 1 month after therapy, she must:
  1. Stop taking Aknenormin (isotretinoin) immediately, if on therapy
  2. Have a pregnancy test at least 19 days after the last act of unprotected heterosexual intercourse
  3. Start using 2 forms of effective contraception simultaneously again for 1 month before resuming Aknenormin (isotretinoin) therapy
  4. Have a second pregnancy test after using 2 forms of effective contraception for 1 month as described above depending on whether she has regular menses or not.

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

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 Aknenormin (isotretinoin). These reports are more frequent for female patients who use only a single method of contraception. Therefore, it is critically important that female patients of childbearing potential use 2 effective forms of contraception simultaneously. Patients must receive written warnings about the rates of possible contraception failure (included in patient education kits).

Using two forms of contraception simultaneously substantially reduces the chances that a female will become pregnant over the risk of pregnancy with either form alone. A drug interaction that decreases effectiveness of hormonal contraceptives has not been entirely ruled out for Aknenormin (see PRECAUTIONS: DRUG INTERACTIONS). 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 1 month after isotretinoin therapy must be reported immediately to the FDA via the MedWatch number 1-800-FDA-1088 and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com).

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

• Must be registered with the iPLEDGE program by the prescriber
• Must understand that severe birth defects can occur with the use of isotretinoin by female patients
• Must be reliable in understanding and carrying out instructions
• Must sign a Patient Information/Informed Consent (for all patients) form that contains warnings about the potential risks associated with isotretinoin
• Must fill and pick up the prescription within 7 days of the date of specimen collection for the pregnancy test for female patients of childbearing potential
• Must fill and pick up the prescription within 30 days of the office visit for male patients and female patients not of childbearing potential
• Must not donate blood while on isotretinoin and for 1 month after treatment has ended
• Must not share isotretinoin with anyone, even someone who has similar symptoms

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

• Must NOT be pregnant or breast-feeding
• Must comply with the required pregnancy testing at a CLIA-certified laboratory
• Must fill and pick up the prescription within 7 days of the date of specimen collection for the pregnancy test
• Must be capable of complying with the mandatory contraceptive measures required for isotretinoin therapy, or commit to continuous abstinence from heterosexual intercourse, and understand behaviors associated with an increased risk of pregnancy
• Must understand that it is her responsibility to avoid pregnancy one month before, during and one month after isotretinoin therapy
• Must have signed an additional Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) form, before starting isotretinoin, that contains warnings about the risk of potential birth defects if the fetus is exposed to isotretinoin
• Must access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654), before starting isotretinoin, on a monthly basis during therapy, and 1 month after the last dose to answer questions on the program requirements and to enter the patient's two chosen forms of contraception
• Must have been informed of the purpose and importance of providing information to the iPLEDGE program should she become pregnant while taking isotretinoin or within 1 month of the last dose

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:

• I know the risk and severity of fetal injury/birth defects from isotretinoin.
• I will train all pharmacists, who participate in the filling and dispensing of isotretinoin prescriptions, on the iPLEDGE program requirements.
• I will comply and seek to ensure all pharmacists who participate in the filling and dispensing of isotretinoin prescriptions comply with the iPLEDGE program requirements described in the booklet entitled Pharmacist Guide for the iPLEDGE Program.
• I will obtain Aknenormin (isotretinoin) product only from iPLEDGE registered wholesalers.
• I will not sell, buy, borrow, loan or otherwise transfer isotretinoin in any manner to or from another pharmacy.
• I will return to the manufacturer (or delegate) any unused product if registration is revoked by the manufacturer or if the pharmacy chooses to not reactivate annually.
• I will not fill isotretinoin for any party other than a qualified patient.

To dispense isotretinoin, the pharmacist must:

1. be trained by the Responsible Site Pharmacist concerning the iPLEDGE program requirements.
2. obtain authorization from the iPLEDGE program via the internet (www.ipledgeprogram.com) or telephone (1-866-495-0654) for every isotretinoin prescription. Authorization signifies that the patient has met all program requirements and is qualified to receive isotretinoin.
3. write the Risk Management Authorization (RMA) number on the prescription.

Aknenormin (isotretinoin) must only be dispensed:

• in no more than a 30-day supply
• with an Aknenormin Medication Guide
• after authorization from the iPLEDGE program
• prior to the “do not dispense to patient after” date provided by the iPLEDGE system (within 30 days of the office visit for male patients and female patients not of childbearing potential and within 7 days of the date of specimen collection for female patients of childbearing potential)
• with a new prescription for refills and another authorization from the iPLEDGE program (No automatic refills are allowed)

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

Aknenormin (isotretinoin) must not be prescribed, dispensed or otherwise obtained through the internet or any other means outside of the iPLEDGE program. Only FDA-approved Aknenormin (isotretinoin) products must be distributed, prescribed, dispensed, and used. Patients must fill Aknenormin (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.

1. The Guide to Best Practices for the iPLEDGE Program includes: isotretinoin teratogenic potential, information on pregnancy testing, and the method to complete a qualified isotretinoin prescription.
2. The iPLEDGE Program Prescriber Contraception Counseling Guide includes: specific information about effective contraception, the limitations of contraceptive methods, behaviors associated with an increased risk of contraceptive failure and pregnancy and the methods to evaluate pregnancy risk.
3. The Pharmacist Guide for the iPLEDGE Program includes: isotretinoin teratogenic potential and the method to obtain authorization to dispense an isotretinoin prescription.
4. The iPLEDGE program is a systematic approach to comprehensive patient education about their responsibilities and includes education for contraception compliance and reinforcement of educational messages. The iPLEDGE program includes information on the risks and benefits of isotretinoin which is linked to the Medication Guide dispensed by pharmacists with each isotretinoin prescription.
5. Female patients not of childbearing potential and male patients, and female patients of childbearing potential are provided with separate booklets. Each booklet contains information on isotretinoin therapy including precautions

Pregnancy Prevention Programme

This medicinal product is TERATOGENIC

Isotretinoin is contraindicated in women of childbearing potential unless all of the following conditions of the Pregnancy Prevention Programme are met:

- She has severe acne (such as nodular or conglobate acne or acne at risk of permanent scarring) resistant to adequate courses of standard therapy with systemic anti-bacterials and topical therapy.

- She understands the teratogenic risk.

- She understands the need for rigorous follow-up, on a monthly basis.

- She understands and accepts the need for effective contraception, without interruption, 1 month before starting treatment, throughout the duration of treatment and 1 month after the end of treatment. At least one and preferably two complementary forms of contraception including a barrier method should be used.

- Even if she has amenorrhea she must follow all of the advice on effective contraception.

- She should be capable of complying with effective contraceptive measures.

- She is informed and understands the potential consequences of pregnancy and the need to rapidly consult if there is a risk of pregnancy.

- She understands the need and accepts to undergo pregnancy testing before, during and 5 weeks after the end of treatment.

- She has acknowledged that she has understood the hazards and necessary precautions associated with the use of isotretinoin.

These conditions also concern women who are not currently sexually active unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy.

The prescriber must ensure that:

- The patient complies with the conditions for pregnancy prevention as listed above, including confirmation that she has an adequate level of understanding.

- The patient has acknowledged the aforementioned conditions.

- The patient has used at least one and preferably two methods of effective contraception including a barrier method for at least 1 month prior to starting treatment and is continuing to use effective contraception throughout the treatment period and for at least 1 month after cessation of treatment.

- Negative pregnancy test results have been obtained before, during and 5 weeks after the end of treatment. The dates and results of pregnancy tests should be documented.

Contraception

Female patients must be provided with comprehensive information on pregnancy prevention and should be referred for contraceptive advice if they are not using effective contraception.

As a minimum requirement, female patients at potential risk of pregnancy must use at least one effective method of contraception. Preferably the patient should use two complementary forms of contraception including a barrier method. Contraception should be continued for at least 1 month after stopping treatment with isotretinoin, even in patients with amenorrhea.

Pregnancy testing

According to local practice, medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL are recommended to be performed in the first 3 days of the menstrual cycle, as follows.

Prior to starting therapy:

In order to exclude the possibility of pregnancy prior to starting contraception, it is recommended that an initial medically supervised pregnancy test should be performed and its date and result recorded. In patients without regular menses, the timing of this pregnancy test should reflect the sexual activity of the patient and should be undertaken approximately 3 weeks after the patient last had unprotected sexual intercourse. The prescriber should educate the patient about contraception.

A medically supervised pregnancy test should also be performed during the consultation when isotretinoin is prescribed or in the 3 days prior to the visit to the prescriber, and should have been delayed until the patient had been using effective contraception for at least 1 month. This test should ensure the patient is not pregnant when she starts treatment with isotretinoin.

Follow-up visits

Follow-up visits should be arranged at 28 day intervals. The need for repeated medically supervised pregnancy tests every month should be determined according to local practice including consideration of the patient's sexual activity and recent menstrual history (abnormal menses, missed periods or amenorrhea). Where indicated, follow-up pregnancy tests should be performed on the day of the prescribing visit or in the 3 days prior to the visit to the prescriber.

End of treatment

Five weeks after stopping treatment, women should undergo a final pregnancy test to exclude pregnancy.

Prescribing and dispensing restrictions

Prescriptions of isotretinoin for women of childbearing potential should be limited to 30 days of treatment and continuation of treatment requires a new prescription. Ideally, pregnancy testing, issuing a prescription and dispensing of isotretinoin should occur on the same day. Dispensing of isotretinoin should occur within a maximum of 7 days of the prescription.

Male patients:

The available data suggest that the level of maternal exposure from the semen of the patients receiving isotretinoin, is not of a sufficient magnitude to be associated with the teratogenic effects of isotretinoin.

Male patients should be reminded that they must not share their medication with anyone, particularly not females.

Additional precautions

Patients should be instructed never to give this medicinal product to another person, and to return any unused capsules to their pharmacist at the end of treatment.

Patients should not donate blood during therapy and for 1 month following discontinuation of isotretinoin because of the potential risk to the foetus of a pregnant transfusion recipient.

Educational material

In order to assist prescribers, pharmacists and patients in avoiding foetal exposure to isotretinoin the Marketing Authorisation Holder will provide educational material to reinforce the warnings about the teratogenicity of isotretinoin, to provide advice on contraception before therapy is started and to provide guidance on the need for pregnancy testing.

Full patient information about the teratogenic risk and the strict pregnancy prevention measures as specified in the Pregnancy Prevention Programme should be given by the physician to all patients, both male and female.

Psychiatric disorders

Depression, depression aggravated, anxiety, aggressive tendencies, mood alterations, psychotic symptoms, and very rarely, suicidal ideation, suicide attempts and suicide have been reported in patients treated with isotretinoin. Particular care needs to be taken in patients with a history of depression and all patients should be monitored for signs of depression and referred for appropriate treatment if necessary. However, discontinuation of isotretinoin may be insufficient to alleviate symptoms and therefore further psychiatric or psychological evaluation may be necessary.

Skin and subcutaneous tissues disorders

Acute exacerbation of acne is occasionally seen during the initial period but this subsides with continued treatment, usually within 7-10 days, and usually does not require dose adjustment.

Exposure to intense sunlight or to UV rays should be avoided. Where necessary a sun-protection product with a high protection factor of at least SPF 15 should be used.

Aggressive chemical dermabrasion and cutaneous laser treatment should be avoided in patients on isotretinoin for a period of 5-6 months after the end of the treatment because of the risk of hypertrophic scarring in atypical areas and more rarely post inflammatory hyper or hypopigmentation in treated areas. Wax depilation should be avoided in patients on isotretinoin for at least a period of 6 months after treatment because of the risk of epidermal stripping.

Concurrent administration of isotretinoin with topical keratolytic or exfoliative anti-acne agents should be avoided as local irritation may increase.

Patients should be advised to use a skin moisturising ointment or cream and a lip balm from the start of treatment as isotretinoin is likely to cause dryness of the skin and lips.

There have been post-marketing reports of severe skin reactions (e.g. erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) associated with isotretinoin use. As these events may be difficult to distinguish from other skin reactions that may occur , patients should be advised of the signs and symptoms and monitored closely for severe skin reactions. If a severe skin reaction is suspected, isotretinoin treatment should be discontinued.

Allergic reactions

Anaphylactic reactions have been rarely reported, in some cases after previous topical exposure to retinoids. Allergic cutaneous reactions are reported infrequently. Serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement have been reported. Severe allergic reactions necessitate interruption of therapy and careful monitoring.

Eye disorders

Dry eyes, corneal opacities, decreased night vision and keratitis usually resolve after discontinuation of therapy. Dry eyes can be helped by the application of a lubricating eye ointment or by the application of tear replacement therapy. Intolerance to contact lenses may occur which may necessitate the patient to wear glasses during treatment.

Decreased night vision has also been reported and the onset in some patients was sudden. Patients experiencing visual difficulties should be referred for an expert ophthalmological opinion. Withdrawal of isotretinoin may be necessary.

Musculo-skeletal and connective tissue disorders

Myalgia, arthralgia and increased serum creatine phosphokinase values have been reported in patients receiving isotretinoin, particularly in those undertaking vigorous physical activity. In some cases, this may progress to potentially life threatening rhabdomyolysis.

Bone changes including premature epiphyseal closure, hyperostosis, and calcification of tendons and ligaments have occurred after several years of administration at very high doses for treating disorders of keratinisation. The dose levels, duration of treatment and total cumulative dose in these patients generally far exceeded those recommended for the treatment of acne.

Benign intracranial hypertension

Cases of benign intracranial hypertension have been reported, some of which involved concomitant use of tetracyclines. Signs and symptoms of benign intracranial hypertension include headache, nausea and vomiting, visual disturbances and papilloedema. Patients who develop benign intracranial hypertension should discontinue isotretinoin immediately.

Hepatobiliary disorders

Liver enzymes should be checked before treatment, 1 month after the start of treatment, and subsequently at 3 monthly intervals unless more frequent monitoring is clinically indicated. Transient and reversible increases in liver transaminases have been reported. In many cases these changes have been within the normal range and values have returned to baseline levels during treatment. However, in the event of persistent clinically relevant elevation of transaminase levels, reduction of the dose or discontinuation of treatment should be considered.

Renal insufficiency

Renal insufficiency and renal failure do not affect the pharmacokinetics of isotretinoin. Therefore, isotretinoin can be given to patients with renal insufficiency. However, it is recommended that patients are started on a low dose and titrated up to the maximum tolerated dose.

Lipid Metabolism

Serum lipids (fasting values) should be checked before treatment, 1 month after the start of treatment, and subsequently at 3 monthly intervals unless more frequent monitoring is clinically indicated. Elevated serum lipid values usually return to normal on reduction of the dose or discontinuation of treatment and may also respond to dietary measures.

Isotretinoin has been associated with an increase in plasma triglyceride levels. Isotretinoin should be discontinued if hypertriglyceridaemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur. Levels in excess of 800 mg/dL or 9 mmol/L are sometimes associated with acute pancreatitis, which may be fatal.

Gastrointestinal disorders

Isotretinoin has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. Patients experiencing severe (hemorrhagic) diarrhoea should discontinue isotretinoin immediately.

Fructose intolerance

Aknenormin contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

High Risk Patients

In patients with diabetes, obesity, alcoholism or a lipid metabolism disorder undergoing treatment with isotretinoin, more frequent checks of serum values for lipids and/or blood glucose may be necessary. Elevated fasting blood sugars have been reported, and new cases of diabetes have been diagnosed during isotretinoin therapy.

Pregnancy Prevention Programme

This medicinal product is TERATOGENIC

Aknenormin is contraindicated in women of childbearing potential unless all of the following conditions of the Pregnancy Prevention Programme are met:

She has severe acne (such as nodular or conglobate acne or acne at risk of permanent scarring) resistant to adequate courses of standard therapy with systemic antibacterials and topical therapy.

She understands the teratogenic risk.

She understands the need for rigorous follow-up, on a monthly basis.

She understands and accepts the need for effective contraception, without interruption, 1 month before starting treatment, throughout the duration of treatment and 1 month after the end of treatment. At least one and preferably two complementary forms of contraception including a barrier method should be used.

Even if she has amenorrhoea she must follow all of the advice on effective contraception.

She should be capable of complying with effective contraceptive measures.

She is informed and understands the potential consequences of pregnancy and the need to rapidly consult if there is a risk of pregnancy.

She understands the need and accepts to undergo pregnancy testing before, during and 5 weeks after the end of treatment.

She has acknowledged that she has understood the hazards and necessary precautions associated with the use of Aknenormin.

These conditions also concern women who are not currently sexually active unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy.

The prescriber must ensure that:

The patient complies with the conditions for pregnancy prevention as listed above, including confirmation that she has an adequate level of understanding.

The patient has acknowledged the aforementioned conditions.

The patient has used at least one and preferably two methods of effective contraception including a barrier method for at least 1 month prior to starting treatment and is continuing to use effective contraception throughout the treatment period and for at least 1 month after cessation of treatment.

Negative pregnancy test results have been obtained before, during and 5 weeks after the end of treatment. The dates and results of pregnancy tests should be documented.

Contraception

Female patients must be provided with comprehensive information on pregnancy prevention and should be referred for contraceptive advice if they are not using effective contraception.

As a minimum requirement, female patients at potential risk of pregnancy must use at least one effective method of contraception. Preferably the patient should use two complementary forms of contraception including a barrier method. Contraception should be continued for at least 1 month after stopping treatment with Aknenormin, even in patients with amenorrhoea.

Pregnancy testing

According to local practice medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL are recommended to be performed in the first 3 days of the menstrual cycle, as follows.

Prior to starting therapy:

In order to exclude the possibility of pregnancy prior to starting contraception, it is recommended that an initial medically supervised pregnancy test should be performed and its date and result recorded. In patients without regular menses, the timing of this pregnancy test should reflect the sexual activity of the patient and should be undertaken approximately 3 weeks after the patient last had unprotected sexual intercourse. The prescriber should educate the patient about contraception.

A medically supervised pregnancy test should also be performed during the consultation when Aknenormin is prescribed or in the 3 days prior to the visit to the prescriber, and should have been delayed until the patient had been using effective contraception for at least 1 month. This test should ensure the patient is not pregnant when she starts treatment with Aknenormin.

Follow-up visits

Follow-up visits should be arranged at 28 day intervals. The need for repeated medically supervised pregnancy tests every month should be determined according to local practice including consideration of the patient's sexual activity and recent menstrual history (abnormal menses, missed periods or amenorrhoea). Where indicated, follow-up pregnancy tests should be performed on the day of the prescribing visit or in the 3 days prior to the visit to the prescriber.

End of treatment

Five weeks after stopping treatment, women should undergo a final pregnancy test to exclude pregnancy.

Prescribing and dispensing restrictions

Prescriptions of Aknenormin for women of childbearing potential should be limited to 30 days of treatment and continuation of treatment requires a new prescription. Ideally, pregnancy testing, issuing a prescription and dispensing of Aknenormin should occur on the same day. Dispensing of Aknenormin should occur within a maximum of 7 days of the prescription.

Male patients

The available data suggest that the level of maternal exposure from the semen of the patients receiving Aknenormin, is not of a sufficient magnitude to be associated with the teratogenic effects of Aknenormin.

Male patients should be reminded that they must not share their medication with anyone, particularly not females.

Additional precautions

Patients should be instructed never to give this medicinal product to another person and to return any unused capsules to their pharmacist at the end of treatment.

Patients should not donate blood during therapy and for 1 month following discontinuation of Aknenormin because of the potential risk to the fetus of a pregnant transfusion recipient.

Educational material

In order to assist prescribers, pharmacists and patients in avoiding fetal exposure to Aknenormin the Marketing Authorisation Holder will provide educational material to reinforce the warnings about the teratogenicity of Aknenormin, to provide advice on contraception before therapy is started and to provide guidance on the need for pregnancy testing.

Full patient information about the teratogenic risk and the strict pregnancy prevention measures as specified in the Pregnancy Prevention Programme should be given by the physician to all patients, both male and female.

Psychiatric disorders

Depression including aggravation of pre-existing depression, anxiety, aggressive tendencies, mood alterations, psychotic symptoms and, very rarely, suicidal ideation, suicide attempts and suicide have been reported in patients treated with Aknenormin. Particular care needs to be taken in patients with a history of depression and all patients should be monitored for signs of depression and referred for appropriate treatment if necessary. However, discontinuation of Aknenormin may be insufficient to alleviate symptoms and therefore further psychiatric or psychological evaluation may be necessary.

Skin and subcutaneous tissues disorders

Acute exacerbation of acne is occasionally seen during the initial period but this subsides with continued treatment, usually within 7-10 days, and usually does not require dose adjustment.

Exposure to intense sunlight or to UV rays should be avoided. Where necessary a sun-protection product with a high protection factor of at least SPF 15 should be used.

Aggressive chemical dermabrasion and cutaneous laser treatment should be avoided in patients on Aknenormin for a period of 5-6 months after the end of the treatment because of the risk of hypertrophic scarring in atypical areas and more rarely post inflammatory hyper or hypopigmentation in treated areas. Wax depilation should be avoided in patients on Aknenormin for at least a period of 6 months after treatment because of the risk of epidermal stripping.

Concurrent administration of Aknenormin with topical keratolytic or exfoliative anti-acne agents should be avoided as local irritation may increase.

Patients should be advised to use a skin moisturising ointment or cream and a lip balm from the start of treatment as Aknenormin is likely to cause dryness of the skin and lips.

There have been post-marketing reports of severe skin reactions (e.g. erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) associated with Aknenormin use. As these events may be difficult to distinguish from other skin reactions that may occur , patients should be advised of the signs and symptoms and monitored closely for severe skin reactions. If a severe skin reaction is suspected, Aknenormin treatment should be discontinued.

Allergic reactions

Anaphylactic reactions have been rarely reported, in some cases after previous topical exposure to retinoids. Allergic cutaneous reactions are reported infrequently. Serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement have been reported. Severe allergic reactions necessitate interruption of therapy and careful monitoring.

Eye disorders

Dry eyes, corneal opacities, decreased night vision and keratitis usually resolve after discontinuation of therapy. Dry eyes can be helped by the application of a lubricating eye ointment or by the application of tear replacement therapy. Intolerance to contact lenses may occur which may necessitate the patient to wear glasses during treatment.

Decreased night vision has also been reported and the onset in some patients was sudden. Patients experiencing visual difficulties should be referred for an expert ophthalmological opinion. Withdrawal of Aknenormin may be necessary.

Musculo-skeletal and connective tissue disorders

Myalgia, arthralgia and increased serum creatine phosphokinase values have been reported in patients receiving Aknenormin, particularly in those undertaking vigorous physical activity. In some cases, this may progress to potentially life threatening rhabdomyolysis.

Bone changes including premature epiphyseal closure, hyperostosis, and calcification of tendons and ligaments have occurred after several years of administration at very high doses for treating disorders of keratinisation. The dose levels, duration of treatment and total cumulative dose in these patients generally far exceeded those recommended for the treatment of acne.

Benign intracranial hypertension

Cases of benign intracranial hypertension have been reported, some of which involved concomitant use of tetracyclines. Signs and symptoms of benign intracranial hypertension include headache, nausea and vomiting, visual disturbances and papilloedema. Patients who develop benign intracranial hypertension should discontinue Aknenormin immediately.

Hepatobiliary disorders

Liver enzymes should be checked before treatment, 1 month after the start of treatment, and subsequently at 3 monthly intervals unless more frequent monitoring is clinically indicated. Transient and reversible increases in liver transaminases have been reported. In many cases these changes have been within the normal range and values have returned to baseline levels during treatment. However, in the event of persistent clinically relevant elevation of transaminase levels, reduction of the dose or discontinuation of treatment should be considered.

Renal insufficiency

Renal insufficiency and renal failure do not affect the pharmacokinetics of Aknenormin. Therefore, Aknenormin can be given to patients with renal insufficiency. However, it is recommended that patients are started on a low dose and titrated up to the maximum tolerated dose.

Lipid Metabolism

Serum lipids (fasting values) should be checked before treatment, 1 month after the start of treatment, and subsequently at 3 monthly intervals unless more frequent monitoring is clinically indicated. Elevated serum lipid values usually return to normal on reduction of the dose or discontinuation of treatment and may also respond to dietary measures.

Aknenormin has been associated with an increase in plasma triglyceride levels. Aknenormin should be discontinued if hypertriglyceridaemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur. Levels in excess of 800 mg/dL or 9 mmol/L are sometimes associated with acute pancreatitis, which may be fatal.

Gastrointestinal disorders

Aknenormin has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. Patients experiencing severe (haemorrhagic) diarrhoea should discontinue Aknenormin immediately.

High risk patients

In patients with diabetes, obesity, alcoholism or a lipid metabolism disorder undergoing treatment with Aknenormin, more frequent checks of serum values for lipids and/or blood glucose may be necessary. Elevated fasting blood sugars have been reported, and new cases of diabetes have been diagnosed during Aknenormin therapy.

Contact with the mouth, eyes and mucous membranes and with abraded skin should be avoided. Care should be taken not to let the medicine accumulate in skin fold areas and in the nasolabial folds.

Due to the irritant nature of Aknenormin gel, caution should be used when applying to sensitive areas of skin, such as the neck, or in patients with concomitant rosacea or perioral dermatitis. Aknenormin should also be used with caution in patients who have had a problem tolerating this or similar retinoid products in the past.

Due to the potential for severe irritation, application to eczematous skin should be avoided.

Aknenormin gel should be used with caution in patients with a history of photoallergy.

As Aknenormin gel may cause increased sensitivity to sunlight, sunlamps should not be used and deliberate or prolonged exposure to sunlight should be avoided or minimised. When exposure to strong sunlight cannot be avoided, patients should be advised to use a sunscreen product and wear protective clothing. Due to the potential for photosensitivity, resulting in greater risk for sunburn, Aknenormin Gel should be used with caution in patients with a personal or family history of skin cancer.

If a patient has sunburn, this should be resolved before using Aknenormin Gel.

Concomitant topical acne therapy should be used with caution because a cumulative irritant effect may occur. If irritancy or dermatitis occur, reduce frequency of application or temporarily interrupt treatment and resume once the irritation subsides. Treatment should be discontinued if the irritation persists.

Butylated hydroxytoluene (BHT) may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

Effects on ability to drive and use machines

Aknenormin could potentially have an influence on the ability to drive and use machines.

A number of cases of decreased night vision have occurred during isotretinoin therapy and in rare instances have persisted after therapy. 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 machines.

Drowsiness, dizziness and visual disturbances have been reported very rarely. Patients should be warned that if they experience these effects, they should not drive, operate machinery or take part in any other activities where the symptoms could put either themselves or others at risk.

Aknenormin could potentially have an influence on the ability to drive and use machines.

A number of cases of decreased night vision have occurred during Aknenormin therapy and in rare instances have persisted after therapy. 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 machines.

Drowsiness, dizziness and visual disturbances have been reported very rarely. Patients should be warned that if they experience these effects, they should not drive, operate machinery or take part in any other activities where the symptoms could put either themselves or others at risk.

Not applicable; the product is a topical preparation which acts locally at the site of application.

Special precautions for disposal and other handling

Return any unused Aknenormin capsules to the Pharmacist.

No special instructions.

There are no special instructions for use or handling of Aknenormin Gel.