Tretinoin

Registered South African indications:

• Induction of remission in acute promyelocytic leukaemia

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to soya or peanut
• Breastfeeding
• Coadministration with vitamin A, tetracyclines, retinoids

Cautions

• Pregnancy
• Renal impairment
• Hepatic impairment
• Woman of childbearing potential
• Children
• History of depression
• Increased body mass index
• Risk factors for QTc prolongation
• Hyperleukocytosis
• Hypercalcaemia
• Risk of thrombosis
• Fructose intolerance
• May impair ability to drive and operate machinery

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

Used for the treatment of

Induction of remission in acute promyelocytic leukaemia (APL: FAB classification AML-M3)
- Previously untreated patients OR patients who relapse after standard chemotherapy (anthracycline and cytosine arabinoside or equivalent therapies) OR patients who are refractory to any chemotherapy

---

Consult specialist for dosages and regimens

---

Capsules should not be chewed

---

To be taken with a meal or shortly thereafter

See adult dosage

---

Dose reduction should be considered for children with toxicity symptoms

---

Capsules should not be chewed

---

To be taken with a meal or shortly thereafter

Pregnancy

• Caution; positive evidence of risk
• Tretinoin is teratogenic. Tretinoin is a retinoid and teratogenic effects have been seen in humans exposed to retinoid drugs.  In humans, there is a limited amount of data from the use of tretinoin in pregnant women but there is a high risk of severe malformation of the foetus, particularly when tretinoin is given during the first trimester
• Tretinoin must not be used during pregnancy, especially during the first trimester, nor in women of childbearing potential not using contraception, unless the clinical condition of the woman (severity of the patient's condition, the urgency of the treatment) requires treatment with tretinoin
• If tretinoin is administered in early pregnancy the patient must be warned of the teratogenic risk of tretinoin and of the risk of severe malformation of the foetus (See Special prescribing points)

Breastfeeding

• Contraindicated
• Breastfeeding must be discontinued if therapy with tretinoin is initiated

Fertility

• There are no data available in humans

Renal Impairment

• Caution; dose adjustment recommended

Hepatic Impairment

• Caution; dose adjustment recommended

Elderly

• No dose adjustment recommended 

Porphyria Information

• Not yet classified (NC)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Increased intracranial pressure
• Dizziness
• Paraesthesia
• Cerebrovascular accident
• Confusional state
• Anxiety
• Depression
• Insomnia
• Mood alterations
• Malaise
• Pseudotumor cerebri
  - headache
  - papilloedema
  - diplopia
  - altered state of consciousness

Cardiovascular Disorders

• Arrhythmia
• Myocardial infarction
• Arterial thrombosis
• Venous thrombosis
• Vasculitis
• Chest pain
• QTc prolongation

Respiratory Disorders

• Respiratory failure
• Nasal dryness
• Asthma

Gastrointestinal Disorders

• Dry mouth
• Nausea and vomiting
• Abdominal pain
• Diarrhoea
• Constipation
• Pancreatitis
• Cheilitis

Hepatobiliary Disorders

• Increased transaminases

Genitourinary Disorders

• Genital ulceration
• Renal infarction

Endocrine and Metabolic Disorders

• Decreased appetite
• Hypercalcaemia

Musculoskeletal Disorders

• Bone pain
• Myositis

Skin and Subcutaneous Tissue Disorders

• Erythema
• Rash
• Pruritus
• Alopecia
• Hyperhidrosis
• Erythema nodosum
• Acute febrile neutrophilic dermatosis (Sweet's syndrome)
• Necrotising fasciitis
• Flushing

Immune, Blood and Lymphatic System Disorders

• Thrombocytosis
• Leukocytosis
• Basophilia (with or without symptomatic hyperhistaminemia)
• Increased blood creatinine
• Increased blood triglyceride
• Increased blood cholesterol
• Chills
• Increased histamine level

Sensory Disorders

• Visual disturbances
• Conjunctival disorders
• Impaired hearing

Others

• Differentiation syndrome (DS)
  - fever
  - dyspnoea
  - acute respiratory distress
  - pulmonary infiltrates
  - hypotension
  - pleural
  - pericardial effusions
  - peripheral oedema
  - weight gain
  - pulmonary, hepatic, renal and multi-organ failure

• Vitamin A
• Other retinoids
• Tetracyclines
• Agents known to cause intracranial hypertension /pseudotumor cerebri
• CYP450 inhibitors
• Ketoconazole
• Cimetidine
• Erythromycin
• Verapamil
• Diltiazem
• Ciclosporin
• CYP450 inducers
• Rifampicin
• Glucocorticoids
• Phenobarbital
• Pentobarbital
• Antifibrinolytic agents
• Tranexamic acid
• Aminocaproic acid
• Aprotinin

• Bone marrow cytology
• Full blood count
• Coagulation profile
• Hepatic function
• Lipid profile

Specific cases may require

• ECG
• Serum calcium
• Respiratory function

Women of childbearing potential / Contraception in females

Therapy with tretinoin should only be started in a female patient of childbearing age if each of the following conditions is met:

• She is informed by her physician of the hazards of becoming pregnant during, and for one month after, treatment with tretinoin
• She is willing to comply with the mandatory contraception measures. It is absolutely essential that every woman of childbearing potential who is to undergo treatment with tretinoin uses a reliable contraception method without interruption during, and for one month after discontinuation of, treatment with tretinoin
• Pregnancy tests must be performed at monthly intervals during therapy

Important warnings

• Differentiation syndrome/Retinoic Acid Syndrome (RAS)
  RAS has been reported in many acute promyelocytic leukaemia patients treated with tretinoin. RAS is now better defined as differentiation syndrome (DS)
• DS is characterized by fever, dyspnoea, acute respiratory distress, pulmonary infiltrates, hypotension, pleural and pericardial effusions, peripheral oedema, weight gain; and may progress to pulmonary, hepatic, renal and multi-organ failure
• Full-blown DS is a life-threatening condition. Early recognition and treatment of DS is therefore of paramount importance. Retinoic acid syndrome is frequently associated with hyperleukocytosis
• An increased body mass index (BMI) has been identified as a predictor factor for DS. Patients with increased BMI should be closely monitored during therapy especially in terms of respiratory functions, diuresis and creatinine levels 

Therapeutic recommendations:

Differentiation syndrome

• Treatment with dexamethasone (10 mg intravenously every 12 hours for a minimum of 3 days or until resolution of the symptoms) must be initiated immediately for patients who present early clinical signs of the syndrome
• In cases of severe DS, temporary interruption of tretinoin therapy should be considered

Hyperleukocytosis

• Patients experiencing hyperleukocytosis should be treated with full-dose anthracycline-based chemotherapy. Immediate treatment of patients with a white blood cell (WBC) count of ≥ 5 x 10⁹/L at diagnosis or at any time during therapy is recommended
• The use of hydroxyurea should be considered for treatment of leukocytosis in patients treated with combination therapy of tretinoin with arsenic trioxide, to keep WBC < 10,000/µL

The mechanism of action of tretinoin may be linked to specific binding of tretinoin to a nuclear retinoic acid receptor (RAR), given that the nuclear receptor alpha of retinoic acid (RARa) is altered in acute promyelocytic leukaemia (APL)  patients by fusion with a protein called PML. Pharmacological doses of tretinoin induce proteolytic degradation of the PML/RARa chimeric protein, a hallmark of APL. Transcriptome analyses suggest that tretinoin may clear PML/RARa from promoters, thereby restoring the wild-type RARa function and releasing the differentiation block.

Capsule 10mg

• Vesanoid-Roche (Roche) originator

Also available in the following forms: Gel and cream.