Isotretinoin

Registered South African indications:

• Severe recalcitrant nodular acne

Isotretinoin is teratogenic. It should not be taken by pregnant women, women intending to become pregnant, or sexually active women in their fertile years, not using at least two methods of contraception, as severe malformations may occur during pregnancy. Isotretinoin is not suitable for breastfeeding mothers. It causes foetal malformations, including hydrocephalus, microcephalus, external ear abnormalities (micropinna, small or absent external auditory canals), microphthalmia, cardiovascular abnormalities, facial dysmorphia, thymus gland abnormalities, parathyroid gland abnormalities with hormone deficiency, and cerebellar malformations. There's also an increased risk of spontaneous abortion. Consequently, its use is contraindicated in pregnant women, those who may become pregnant during treatment, and in all women of childbearing potential unless they use effective contraception continuously for one month before, during, and at least one month after treatment. Even females with a history of infertility (except after a hysterectomy) or who claim no sexual activity must use effective contraceptive measures while on isotretinoin, as per guidelines. It's advised to use two reliable forms of contraception simultaneously. Isotretinoin is contraindicated in women of childbearing potential unless they meet these conditions: severe nodular acne resistant to standard therapies, understanding and compliance with instructions, informed of pregnancy risks during and one month after isotretinoin treatment, aware of contraception failure risks, understands precautions, capable of adhering to mandatory contraception, using effective contraception without interruption for one month before starting isotretinoin, during therapy, and for one month after discontinuation. The efficacy of contraceptive methods, especially in the first cycle, should be carefully considered, with additional methods advised. A negative pregnancy test result within 11 days before starting therapy and monthly testing during treatment are strongly recommended. Treatment should only start on the 2nd or 3rd day of the next normal menstrual period. In relapse cases, the same uninterrupted contraceptive measures and pregnancy evaluations are required. The patient must understand and commit to these contraceptive measures. Pregnancy during isotretinoin treatment or within the first month after discontinuation carries an extremely high risk of severe foetal malformation. Every precaution must be taken to ensure the patient is not pregnant before, during, and for one month after therapy. To assist in avoiding foetal exposure to isotretinoin, the manufacturer provides a Pregnancy Prevention Programme, including a Patient Information Brochure, Brochure on Birth Control, Female Patient Information and Consent Form, Physician’s Guide to Prescription, and Physician’s Checklist for Prescription to Females. This information should be provided to patients both orally and in writing.

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to peanut or soya
• Pregnancy (see boxed warning)
• Breastfeeding (see boxed warning)
• Women of childbearing potential unless taking contraceptive measures
• Pre-existing hypervitaminosis A
• Hepatic insufficiency
• Patients with excessively elevated blood lipid values
• Supplementary treatment with tetracyclines is contraindicated

South African recommendations

• Renal impairment
• Elderly

Handling of isotretinoin

• Patients should be reminded that isotretinoin is a scheduled medicine and not a cosmetic agent and that it is a criminal act to transfer it to or share with any person not in possession of a valid prescription
• Isotretinoin should only be prescribed by medical practitioners experienced in the use of systemic retinoids and who understand the risk of teratogenicity associated with its use

Hepatotoxicity

• Monitor liver function before, 1 month after starting, and every 3 months
• Consider dose reduction or discontinuation if liver enzymes elevate significantly or hepatitis is suspected

Psychiatric disorders

• Monitor for depression, anxiety, aggressive tendencies, mood changes, psychosis, suicidal thoughts
• Extra care in patients with a history of depression

Pseudotumor cerebri

• Screen for papilloedema in symptoms like headache, nausea, vomiting, visual disturbances
• Avoid use with tetracyclines

Visual impairment

• Monitor for corneal opacities, dry eyes, decreased night vision, keratitis
• Caution with driving at night
• Consider withdrawal if visual problems occur

Lipids

• Check serum lipids before, 1 month after starting, and at end of therapy
• Discontinue if significant hypertriglyceridemia or pancreatitis symptoms occur

Musculoskeletal disorders

• Possible myalgia, arthralgia, increased serum creatine phosphokinase, especially in physically active patients
• Skeletal hyperostosis and premature epiphyseal closure in high-dose, long-term use

Gastrointestinal disorders

• Risk of inflammatory bowel disease
• Discontinue in severe diarrhoea

Unused capsules

• Patients should be instructed never to give isotretinoin to another person and to return any unused capsules to their pharmacist at the end of treatment

Blood donation

• 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

Skin and subcutaneous tissues disorders

• Acute exacerbation of acne may occur initially
• Avoid intense UV exposure and aggressive skin treatments. Use sun protection with SPF 15 or higher
• Use skin moisturizers and lip balms to manage dryness
• Avoid aggressive chemical dermabrasion and cutaneous laser treatment for 5 - 6 months post-treatment due to scarring risks
• Avoid wax depilation for at least 6 months post-treatment due to risk of epidermal stripping
• Concurrent use with topical keratolytic or exfoliative anti-acne agents not recommended
• Watch for severe skin reactions like erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis

Allergic reactions

• Discontinue in severe allergic reactions

Sorbitol/mannitol intolerance

• Not suitable for patients with sorbitol/mannitol intolerance

High-risk patients

• Frequent monitoring of serum lipids and blood glucose in patients with diabetes, obesity, alcoholism, or lipid metabolism disorder

Driving and machinery use

• Caution advised due to potential decreased night vision, which can be sudden
• Persisting vision issues possible post-therapy
• Exercise caution when driving or operating machinery

Forms avail. in SA and covered in this monograph: cap

South African registered indications and dosages

The initial diagnosis and prescription of isotretinoin should be performed by a dermatologist with expertise in the use of systemic retinoids for the treatment of severe acne and a full understanding of the risks of isotretinoin therapy and monitoring requirements. The therapeutic response to isotretinoin and its adverse events are dose-related, and vary between patients. This necessitates individual dosage adjustment during therapy

Severe recalcitrant nodular acne
- Reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics

10mg, 20mg & 40mg Capsule

• Oral (cap): Initial: 0.5mg/kg/day, in 1-2 divided doses; Dose range for most patients: 0.5-1mg/kg/day, in 1-2 divided doses; Severe disease or truncal acne may require higher daily doses: Up to 2mg/kg/day in 1-2 divided doses; Treatment duration: Varies as a function of the daily dose, with complete remission often achieved by a therapy course of 16-24 weeks

8mg & 16mg Capsule

• Oral (cap): Initial: 0.4mg/kg/day, in 1-2 divided doses; Dose range for most patients: 0.4-0.8mg/kg/day, in 1-2 divided doses; Severe disease or truncal acne may require higher daily doses: Up to 1.6mg/kg/day, in 1-2 divided doses; Treatment duration: Varies as a function of the daily dose, with complete remission often achieved by a therapy course of 16-24 weeks

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Formulations may have differing posology, where a max dose of 1mg/kg/day to be given for a limited period of time is recommended (A cumulative treatment dose of 120-150mg/kg has been documented to increase remission rates and prevent relapse). Refer to product specific information in this regard

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In severe recalcitrant nodular acne, nodules are inflamed lesions ≥5mm. The nodules may become suppurative or haemorrhagic. “Severe”, by definition, means “many” as opposed to “few or several” nodules

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In cases where patients exhibit severe intolerance to the recommended dose, treatment can be continued at a lower dose, potentially extending the duration of therapy. Most patients achieve complete acne clearance after a single course of treatment. If there's a definite relapse, a second course of isotretinoin can be administered using the same daily dosage as before. However, as improvements in acne can continue up to 8 weeks post-treatment, any re-treatment should be delayed until after this observation period

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Concurrent topical therapy
Concurrent administration of other keratolytic or exfoliative anti-acne agents is not indicated. Nor is concurrent radiation therapy with ultraviolet light indicated. Patients should avoid exposure to the sun. Adjuvant therapy with mild topical medicines may be given, as required

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Method of administration: The capsules should be taken with food, once or twice daily

Paed. forms avail. in SA and covered in this monograph: cap

South African registered indications and dosages

The initial diagnosis and prescription of isotretinoin should be performed by a dermatologist with expertise in the use of systemic retinoids for the treatment of severe acne and a full understanding of the risks of isotretinoin therapy and monitoring requirements. The therapeutic response to isotretinoin and its adverse events are dose-related, and vary between patients. This necessitates individual dosage adjustment during therapy

Severe recalcitrant nodular acne
- Reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics

8mg & 16mg Capsule

Younger than 12 years

• Not established for use

Older than 12 years 

• Oral (cap): Initial: 0.4mg/kg/day in 1-2 divided doses; Dose range for most patients: 0.4-0.8mg/kg/day in 1-2 divided doses; Treatment duration: Varies as a function of the daily dose, with complete remission often achieved by a therapy course of 16-24 weeks

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Isotretinoin should not be used for the treatment of prepubertal acne and is not recommended in children less that 12 years of age due to lack of data on efficacy and safety

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In severe recalcitrant nodular acne, nodules are inflamed lesions ≥5mm. The nodules may become suppurative or haemorrhagic. “Severe”, by definition, means “many” as opposed to “few or several” nodules

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In cases where patients exhibit severe intolerance to the recommended dose, treatment can be continued at a lower dose, potentially extending the duration of therapy. Most patients achieve complete acne clearance after a single course of treatment. If there's a definite relapse, a second course of isotretinoin can be administered using the same daily dosage as before. However, as improvements in acne can continue up to 8 weeks post-treatment, any re-treatment should be delayed until after this observation period

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Concurrent topical therapy
Concurrent administration of other keratolytic or exfoliative anti-acne agents is not indicated. Nor is concurrent radiation therapy with ultraviolet light indicated. Patients should avoid exposure to the sun. Adjuvant therapy with mild topical medicines may be given, as required

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Method of administration: The capsules should be taken with food, once or twice daily

Pregnancy 

South African recommendations

• Contraindicated
• Isotretinoin is teratogenic. It should not be taken by pregnant women, women intending to become pregnant, or sexually active women in their fertile years, not using at least two methods of contraception, as severe malformations may occur during pregnancy. Pregnancy is an absolute contraindication to treatment with isotretinoin. If pregnancy does occur in spite of the detailed precautions during treatment with isotretinoin or in the month following therapy, there is a great risk of very severe and serious malformation of the foetus (see boxed warning)
• Medically supervised pregnancy tests with a minimum sensitivity of 25mIU/mL are recommended within the first 3 days of the menstrual cycle, as follows
  - Prior to starting therapy: Initial medically supervised pregnancy tests should be performed before starting contraception to exclude the possibility of pregnancy. The date and result should be recorded. For patients without regular menses, this test should be about 3 weeks after the last unprotected sexual intercourse, reflecting the patient's sexual activity. Patients should be educated about contraception
  - Another medically supervised pregnancy test should be done when isotretinoin is prescribed or in the 3 days prior to the prescriber's visit, after at least 1 month of effective contraception use. This ensures the patient is not pregnant when starting isotretinoin treatment
• Follow-up visits
  - Arranged at 28-day intervals. The need for monthly medically supervised pregnancy tests depends on local practice, sexual activity, and menstrual history (e.g., irregular menses, missed periods, amenorrhea). When indicated, follow-up tests should occur on the day of the prescribing visit or in the 3 days before it
• End of treatment
  - A final pregnancy test is recommended five weeks after stopping treatment to confirm the absence of pregnancy
• Prescriptions for isotretinoin in women of childbearing potential should be limited to 30 days, requiring a new prescription for continued treatment
• Ideally, pregnancy testing, prescribing, and dispensing of isotretinoin should occur on the same day, with dispensing within 7 days of the prescription
• Male patients: Data suggests that maternal exposure from the semen of patients receiving isotretinoin is not significant enough to cause teratogenic effects. Male patients are reminded not to share their medication, especially with females

Breastfeeding

South African recommendations

• Contraindicated
• Isotretinoin may not be given to breastfeeding mothers
• Isotretinoin is highly lipophilic, therefore the passage of isotretinoin into human milk is very likely. Due to the potential for adverse effects in the child exposed via mothers' milk, isotretinoin is contraindicated during breastfeeding 

Fertility

South African recommendations

• Isotretinoin, in therapeutic dosages, does not affect the number, motility and morphology of sperm and does not jeopardise the formation and development of the embryo on the part of the men taking isotretinoin

South African recommendations

• Caution; dose adjustment recommended
  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
  In patients with severe renal insufficiency, treatment should be started at a lower dose (e.g. 8mg/day); Increased up to 0.8mg/kg/day or until the patient is receiving the maximum tolerated dose

South African recommendations

• Contraindicated

South African recommendations

• Caution; dose adjustment recommended
  8mg & 16mg cap: Initial: 0.4mg/kg/day in 1-2 divided doses; Dose range for most patients: 0.4-0.8mg/kg/day in 1-2 divided doses; Treatment duration: Varies as a function of the daily dose, with complete remission often achieved by a therapy course of 16-24 weeks

Infections and Infestations

Less frequent

• Gram positive (mucocutaneous) bacterial infection

Blood and Lymphatic System Disorders

Frequent

• Anaemia
• Increased red blood cell sedimentation rate
• Thrombocytopenia
• Thrombocytosis
• Neutropenia

Less frequent

• Lymphadenopathy

Immune System Disorders

Less frequent

• Allergic skin reaction
• Anaphylactic reactions
• Hypersensitivity

Metabolism and Nutrition Disorders

Less frequent

• Diabetes mellitus
• Hyperuricaemia

Psychiatric Disorders

Less frequent

• Depression
• Aggravated depression
• Aggressive tendencies
• Anxiety
• Mood alterations
• Abnormal behaviour
• Psychotic disorder
• Suicidal ideation
• Suicide attempt
• Suicide

Nervous System Disorders

Frequent

• Headache

Less frequent

• Benign intracranial hypertension
• Convulsions
• Drowsiness
• Dizziness

Eye Disorders

Frequent

• Blepharitis
• Conjunctivitis
• Dry eye
• Eye irritation

Less frequent

• Blurred vision
• Cataract
• Colour blindness
• Contact lens intolerance
• Corneal opacity
• Decreased night vision
• Keratitis
• Papilloedema
• Photophobia
• Visual disturbances

Ear and Labyrinth Disorders

Less frequent

• Impaired hearing

Vascular Disorders

Less frequent

• Vasculitis (for example Wegener's granulomatosis allergic vasculitis)

Respiratory, Thoracic and Mediastinal Disorders

Frequent

• Epistaxis
• Nasal dryness
• Nasopharyngitis

Less frequent

• Bronchospasm (particularly in patients with asthma)
• Hoarseness

Gastrointestinal Disorders

Less frequent

• Colitis
• Ileitis
• Dry throat
• Gastrointestinal haemorrhage
• Haemorrhagic diarrhoea
• Inflammatory bowel disease
• Nausea
• Pancreatitis

Hepatobiliary Disorders

Frequent

• Increased transaminase

Less frequent

• Hepatitis

Skin and Subcutaneous Tissues Disorders

Frequent

• Cheilitis
• Dermatitis
• Dry skin
• Localised exfoliation
• Pruritus
• Erythematous rash
• Skin fragility

Less frequent

• Alopecia
• Acne fulminans
• Aggravated acne
• Erythema
• Exanthema
• Hair disorders
• Hirsutism
• Nail dystrophy
• Paronychia
• Photosensitivity reaction
• Pyogenic granuloma
• Skin hyperpigmentation
• Increased sweating

Not known

• Erythema multiforme
• Steven-Johnson Syndrome
• Toxic epidermal necrolysis

Musculo-skeletal and Connective Tissue Disorders

Frequent

• Arthralgia
• Myalgia
• Back pain (particularly in adolescents)

Less frequent

• Arthritis
• Calcinosis
• Epiphyses premature fusion
• Exostosis
• Reduced bone density
• Tendonitis

Unknown

• Rhabdomyolysis

Renal and Urinary Disorders

Less frequent

• Glomerulonephritis

Reproductive System and Breast Disorders

Unknown

• Sexual dysfunction
• Erectile dysfunction
• Decreased libido
• Gynaecomastia
• Vulvovaginal dryness

General Disorders and Administration Site Conditions

Less frequent

• Increased formation of granulation tissue
• Malaise

Investigations

Frequent

• Increased blood triglycerides
• Decreased high density lipoprotein

Less frequent

• Increased blood cholesterol
• Increased blood glucose
• Haematuria
• Proteinuria

Unknown

• Increased blood creatine phosphokinase

• Topical keratolytic
• Exfoliative anti-acne agents
• Vitamin A
• Tetracyclines

• Full blood count
• Erythrocyte sedimentation rate
• Creatine phosphokinase
• Mental status
• Pregnancy test
• Lipid profile
• Hepatic function
• Glucose

Isotretinoin is a synthetic stereoisomer of all-trans retinoic acid (tretinoin). The mechanism of action of isotretinoin has not been elucidated, but the action is associated with dose-related 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.

Capsule 10mg

• Acnetane (Adcock)
• Acnetret (Cipla Medpro)
• Apex Isotretinoin (Cipla)
• Oratane 10mg (Acino Pharma)
• Roaccutane (Roche) originator

Capsule 20mg

• Acnetane (Adcock)
• Acnetret (Cipla Medpro)
• Apex Isotretinoin (Cipla)
• Oratane 20mg (Acino Pharma)
• Roaccutane (Roche) originator

Capsule 40mg

• Oratane 40mg (Acino Pharma)

Also available in the following form: Gel.