Tretinoin (Systemic)

Name: Tretinoin (Systemic)

What do I need to tell my doctor BEFORE I take Tretinoin?

  • If you have an allergy to tretinoin, vitamin A, or any other part of tretinoin.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you are breast-feeding. Do not breast-feed while you take this medicine.
  • If you are taking any of these drugs: Demeclocycline, doxycycline, minocycline, tetracycline, a product that has vitamin A in it, a product that is like vitamin A, or St. John's wort.

This is not a list of all drugs or health problems that interact with tretinoin.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
  • Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
  • Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
  • Change in hearing.
  • Hearing loss.
  • Swelling of belly.
  • A heartbeat that does not feel normal.
  • A burning, numbness, or tingling feeling that is not normal.
  • Low mood (depression).
  • Swelling, warmth, numbness, change of color, or pain in a leg or arm.
  • Chest pain or pressure.
  • Very bad belly pain.
  • Shortness of breath, a big weight gain, or swelling in the arms or legs.
  • Feeling confused.
  • Hallucinations (seeing or hearing things that are not there).

How do I store and/or throw out Tretinoin?

  • Store at room temperature.
  • Protect from light.
  • Protect from heat.
  • Store in a dry place. Do not store in a bathroom.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Check with your pharmacist about how to throw out unused drugs.

Pronunciation

(TRET i noyn)

Dosing Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dietary Considerations

The absorption of retinoids (as a class) is enhanced when taken with food. Capsule contains soybean oil.

Adverse Reactions

Most patients will experience drug-related toxicity, especially headache, fever, weakness and fatigue. These are seldom permanent or irreversible and do not typically require therapy interruption.

>10%:

Cardiovascular: Peripheral edema (52%), chest discomfort (32%), edema (29%), cardiac arrhythmia (23%), flushing (23%), hypotension (14%), hypertension (11%), localized phlebitis (11%)

Central nervous system: Headache (86%), malaise (66%), shivering (63%), pain (37%), dizziness (20%), anxiety (17%), paresthesia (17%), depression (14%), insomnia (14%), confusion (11%)

Dermatologic: Xeroderma (≤77%), skin rash (54%), diaphoresis (20%), pruritus (20%), alopecia (14%), skin changes (14%)

Endocrine & metabolic: Hypercholesterolemia (≤60%), hypertriglyceridemia (≤60%), weight gain (23%), weight loss (17%)

Gastrointestinal: Dry mucous membranes (≤77%), nausea (≤57%), vomiting (≤57%), gastrointestinal hemorrhage (34%), abdominal pain (31%), mucositis (26%), diarrhea (23%), anorexia (17%), constipation (17%), dyspepsia (14%), abdominal distention (11%)

Hematologic & oncologic: Hemorrhage (60%), leukocytosis (40%), disseminated intravascular coagulation (26%)

Hepatic: Increased liver enzymes (50% to 60%)

Infection: Infection (58%)

Neuromuscular & skeletal: Ostealgia (77%), APL differentiation syndrome (≤25%), myalgia (14%)

Ophthalmic: Eye disease (17%), visual disturbance (17%)

Otic: Otalgia (23%; ear fullness)

Renal: Renal insufficiency (11%)

Respiratory: Upper respiratory complaint (63%), dyspnea (60%), respiratory insufficiency (26%), pleural effusion (20%), pneumonia (14%), rales (14%), wheezing (expiratory: 14%)

Miscellaneous: Fever (83%)

1% to 10%:

Cardiovascular: Cardiac failure (6%), facial edema (6%), cardiomegaly (3%), cardiomyopathy (3%), cerebrovascular accident (3%), heart murmur (3%), ischemia (3%), myocardial infarction (3%), myocarditis (3%), pericarditis (3%)

Central nervous system: Agitation (9%), cerebral hemorrhage (9%), flank pain (9%), intracranial hypertension (9%), hallucination (6%), abnormal gait (3%), agnosia (3%), aphasia (3%), asterixis (3%), ataxia (3%), brain disease (3%), cerebral edema (cerebellar: 3%), central nervous system depression (3%), coma (3%), dementia (3%), drowsiness (3%), dysarthria (3%), facial paralysis (3%), forgetfulness (3%), hemiplegia (3%), hyporeflexia (3%), hypothermia (3%), loss of consciousness (3%), seizure (3%), speech disturbance (3%)

Dermatologic: Cellulitis (8%), pallor (6%)

Endocrine & metabolic: Disturbance in fluid balance (6%), acidosis (3%)

Gastrointestinal: Gastrointestinal ulcer (3%)

Genitourinary: Dysuria (9%), benign prostatic hypertrophy (3%), urinary frequency (3%)

Hematologic & oncologic: Lymphatic disease (6%)

Hepatic: Hepatosplenomegaly (9%), ascites (3%), hepatitis (3%)

Local: Local inflammation (bone: 3%)

Neuromuscular & skeletal: Lower extremity weakness (3%), myelopathy (3%), tremor (3%)

Ophthalmic: Decreased visual acuity (6%), decreased pupillary reflex (3%), visual field defect (3%)

Otic: Hearing loss (6%; may be irreversible)

Renal: Acute renal failure (3%), renal tubular necrosis (3%)

Respiratory: Lower respiratory signs and symptoms (9%), pulmonary infiltrates (6%), asthma (3%), laryngeal edema (3%), pulmonary hypertension (3%)

<1% (Limited to important or life-threatening): Arterial thrombosis, basophilia, erythema nodosum, histamine release (hyperhistaminemia), hypercalcemia, hypersensitivity angiitis, myositis, pancreatitis, pseudotumor cerebri, renal infarction, Sweet's syndrome, thrombocythemia, ulcer (genital), venous thrombosis

Warnings/Precautions

Concerns related to adverse effects:

• APL differentiation syndrome: [US Boxed Warning]: About 25% of patients with APL treated with tretinoin have experienced APL differentiation syndrome (formerly called retinoic-acid-APL [RA-APL] syndrome), which is characterized by fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, and pleural or pericardial effusions, edema, and hepatic, renal, and/or multiorgan failure. The syndrome may be accompanied by impaired myocardial contractility and episodic hypotension. It has been observed with or without concomitant leukocytosis. Intubation and mechanical ventilation have been required in some cases due to progressive hypoxemia; fatalities due to multiorgan failure have occurred. The syndrome generally occurs during the first month of treatment, with some cases reported following the first dose. Management has not been defined, although high-dose steroids given at the first suspicion appear to reduce morbidity and mortality. Regardless of the leukocyte count, at the first signs suggestive of APL differentiation syndrome (eg, unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatory findings, radiographic abnormalities), immediately initiate corticosteroid therapy with dexamethasone 10 mg IV every 12 hours for 3 to 5 days (or until the symptoms resolve); taper off over 2 weeks. Most patients do not require termination of tretinoin therapy during treatment of the APL differentiation syndrome.

• Cardiovascular effects: Venous thrombosis and MI have been reported in patient without risk factors for thrombosis or MI. The risk for thrombosis (arterial and venous) is increased during the first month of treatment. Use with caution with antifibrinolytic agents; thrombotic complications have been reported (rarely) with concomitant use.

• CNS effects: May cause headache, malaise, and/or dizziness; caution patients about performing tasks which require mental alertness (eg, operating machinery or driving).

• Leukocytosis: [US Boxed Warning]: During treatment, ~40% of patients will develop rapidly evolving leukocytosis. Patients who present with a high WBC at diagnosis (>5,000/mm3) are at increased risk of further rapid increase in WBC counts. Rapidly evolving leukocytosis is associated with a higher risk of life-threatening complications. Initiate treatment with high-dose corticosteroids immediately if signs and symptoms of APL differentiation syndrome are present with leukocytosis. Chemotherapy may be added to tretinoin treatment in patients presenting with a WBC count >5,000/mm3 or for a rapid WBC increase in patients leukopenic at start of treatment (may result in a lower incidence of APL differentiation syndrome). Consider adding full-dose chemotherapy (including an anthracycline if not contraindicated) to tretinoin therapy on day 1 or 2 for patients presenting with a WBC count >5,000/mm3; immediately add for patients presenting with a WBC count <5,000/mm3 if the WBC count reaches ≥6,000/mm3 by day 5, ≥10,000/mm3 by day 10, or ≥15,000/mm3 by day 28.

• Lipid effects: Up to 60% of patients experienced hypercholesterolemia or hypertriglyceridemia, which were reversible upon completion of treatment.

• Liver function test abnormalities: Elevated liver function test results occur in 50% to 60% of patients during treatment. Carefully monitor liver function test results during treatment and give consideration to a temporary withdrawal of tretinoin if test results reach >5 times the upper limit of normal. Most liver function test abnormalities will resolve without interruption of treatment or after therapy completion.

• Pseudotumor cerebri: Retinoids have been associated with pseudotumor cerebri (benign intracranial hypertension), especially in children. Concurrent use of other drugs associated with this effect (eg, tetracyclines) may increase risk. Early signs and symptoms include papilledema, headache, nausea, vomiting, visual disturbances, intracranial noises, or pulsate tinnitus.

Disease-related concerns:

• APL: Tretinoin treatment for APL should be initiated early, discontinue if pending cytogenetic analysis does not confirm APL by t(15;17) translocation or the presence of the PML/RARα fusion protein (caused by translocation of the promyelocytic [PML] gene on chromosome 15 and retinoic acid receptor [RAR] alpha gene on chromosome 17).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.

Special populations:

• Pregnancy: [US Boxed Warning]: High risk of teratogenicity; if treatment with tretinoin is required in women of childbearing potential, two reliable forms of contraception should be used during and for 1 month after discontinuation of treatment, unless abstinence is the chosen method. Within 1 week prior to starting therapy, serum or urine pregnancy test (sensitivity at least 50 milliunits/mL) should be collected. If possible, delay therapy until results are available. Repeat pregnancy testing and contraception counseling monthly throughout the period of treatment. Microdosed progesterone products (“minipill”) may provide inadequate pregnancy protection. Repeat pregnancy testing and contraception counseling monthly throughout the period of treatment. If possible, initiation of treatment with tretinoin should be delayed until negative pregnancy test result is confirmed.

Dosage form specific issues:

• Product interchange: Tretinoin (which is also known as all-trans retinoic acid, or ATRA) and isotretinoin may be confused, while both products may be used in cancer treatment, they are not interchangeable; verify product prior to dispensing and administration to prevent medication errors.

Other warnings/precautions:

• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician. Patients with APL are at high risk and can have severe adverse reactions to tretinoin. Administer tretinoin only to patients with APL under the close supervision of a provider who is experienced in the management of patients with acute leukemia, and in a facility with laboratory and supportive services for appropriate monitoring.

Pregnancy Risk Factor D Pregnancy Considerations

Adverse events were observed in animal reproduction studies. [US Boxed Warning]: High risk of teratogenicity; if treatment with tretinoin is required in women of childbearing potential, two reliable forms of contraception should be used simultaneously during and for 1 month after discontinuation of treatment, unless abstinence is the chosen method. Within 1 week prior to starting therapy, serum or urine pregnancy test (sensitivity at least 50 milliunits/mL) should be collected. If possible, delay therapy until results are available. Repeat pregnancy testing and contraception counseling monthly throughout the period of treatment. Contraception must be used even when there is a history of infertility or menopause, unless a hysterectomy has been performed. Tretinoin was detected in the serum of a neonate at birth following maternal use of standard doses during pregnancy (Takitani 2005). Use in humans for the treatment of acute promyelocytic leukemia (APL) is limited and exposure occurred after the first trimester in most cases (Valappil 2007). However, major fetal abnormalities and spontaneous abortions have been reported with other retinoids; some of these abnormalities were fatal. If the clinical condition of a patient presenting with APL during pregnancy warrants immediate treatment, tretinoin use should be avoided in the first trimester; treatment with tretinoin may be considered in the second and third trimester with careful fetal monitoring, including cardiac monitoring (Sanz 2009).

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