Hematologic |
3.13.1) SUMMARY
A) Hyperleukocytosis is a common occurrence following treatment with oral tretinoin.
B) Disseminated intravascular coagulation, thrombosis, and thrombocytosis are uncommon occurrences that have been associated with oral tretinoin therapy.
3.13.2) CLINICAL EFFECTS
A) LEUKOCYTOSIS 1) WITH THERAPEUTIC USE a) Hyperleukocytosis has been reported following oral tretinoin therapy to treat acute promyelocytic leukemia. In most cases, leukocytosis of greater than 20 x 10(9)/L may precede development of the "retinoic acid syndrome" and may occur in 50% of patients treated with tretinoin (Ruiz-Arguelles et al, 1995; Shimoni et al, 1995; Mahendra et al, 1994; Chanarin et al, 1993; De Lacerda et al, 1993; Mahmoud et al, 1993; Frankel et al, 1992; Lopez & Hayne, 1992; Roberts et al, 1992; Runde et al, 1992; Van der Hem & Ossenkoppele, 1992).
b) CASE REPORT: Two cases of hyperleukocytosis occurred one week after initiation of oral tretinoin therapy, 175 mg/m(2) of body surface area, to treat metastatic non-small cell lung cancer (Kahn et al, 1992).
c) INCIDENCE: In a study determining the effectiveness of low-dose tretinoin in acute promyelocytic leukemia, 9 out of 30 patients developed hyperleukocytosis following oral tretinoin 25 mg/m(2) of body surface area/day. The hyperleukocytosis occurred between days 10 and 23 of therapy and the WBC count was 14 to 43 x 10(9)/L (Castaigne et al, 1993).
B) DISSEMINATED INTRAVASCULAR COAGULATION 1) WITH THERAPEUTIC USE a) INCIDENCE: Approximately 26% of patients have developed disseminated intravascular coagulation (DIC) following oral tretinoin therapy for acute promyelocytic leukemia (Prod Info VESANOID(R) oral capsules, 2004). b) CASE REPORT: A 39-year-old male, with DIC prior to oral tretinoin therapy, experienced an exacerbation of DIC 38 days after initiation of oral tretinoin therapy, 60 mg/m(2) body surface area. 1) The patient's serum fibrinogen-fibrin degradation products-E (FDP-E) increased, indicating DIC. There was painful swelling of the patient's legs due to thrombophlebitis.
2) Eighteen days after the cessation of tretinoin therapy, the patient's serum FDP-E decreased to normal values and the leg pain rapidly resolved (Shibata et al, 1994).
C) THROMBOEMBOLUS 1) WITH THERAPEUTIC USE a) CASE REPORT: A 29-year-old male developed clinical signs of an acute thrombosis of the right arm and thrombophlebitic lesions of both legs seven days after beginning oral tretinoin therapy. The thrombosis and thrombophlebitic lesions resolved with heparin therapy (Runde et al, 1992). b) CASE REPORT: A 32-year-old male developed deep venous thrombosis of the right vein and thrombophlebitis of the right forearm 12 days after discontinuation of oral tretinoin therapy, 45 mg/m(2) body surface area/day for 12 days. The thrombosis completely resolved after 14 days of heparin therapy (De Lacerda et al, 1993). 1) Tretinoin appeared to cause multiple thrombi by decreasing fibrinolysis and inducing a hypercoagulable state. In patients with tretinoin-induced hyperleukocytosis and undergoing cytotoxic chemotherapy, prophylactic heparin may prevent the development of a thrombosis (De Lacerda et al, 1993).
c) CASE REPORT: Fatal thrombosis, involving multiple organs, occurred in a 47-year-old woman undergoing oral tretinoin therapy 45 mg/m(2) body surface area/day. The patient died, six days after initiation of tretinoin therapy, due to progressive hepatic, respiratory, and renal failure secondary to extensive thromboses (Brouns et al, 1994). D) THROMBOCYTOSIS 1) WITH THERAPEUTIC USE a) CASE REPORT: Thrombocytosis with a platelet count of 1071 x 10(9)/L was reported in a 49-year-old patient receiving all-trans retinoic acid (ATRA) for treatment of acute promyelocytic leukemia. ATRA was discontinued and the patient's platelet count normalized 56 days later (Kentos et al, 1997).
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Dermatologic |
3.14.1) SUMMARY
A) Dermal changes, following oral or topical tretinoin use, may include contact dermatitis, dermatosis, lip and skin dryness, scarring, and alopecia.
B) Facial flushing has been reported following oral therapeutic administration of 9-cis retinoic acid.
3.14.2) CLINICAL EFFECTS
A) DERMATITIS 1) WITH THERAPEUTIC USE a) Contact dermatitis was observed following chronic therapeutic use of topical tretinoin. An allergic reaction to the tretinoin was determined to be the cause of the dermatitis (Balato et al, 1995; Tosti et al, 1992) Rudzki & Grzyua, 1978; Nordquist & Mehr, 1977; (Jordan et al, 1975).
b) Approximately 54% of patients ingesting tretinoin experienced rashes, and 20% of patients experienced pruritus (Prod Info VESANOID(R) oral capsules, 2004).
B) SKIN NODULE 1) WITH THERAPEUTIC USE a) An acute febrile neutrophilic dermatosis, called Sweet's syndrome, was diagnosed in a patient receiving oral tretinoin, 80 mg/day. The syndrome is characterized by acute onset of inflammatory skin nodules, malaise, fever, and neutrophilia. The patient developed the skin nodules on her arms. She was treated with intravenous methylprednisolone, 1 g daily for 3 days, with resolution of the skin lesions and fever (Cox & O'Brien, 1994).
C) DRY SKIN 1) WITH THERAPEUTIC USE a) Lip and skin dryness, with concomitant hypercalcemia, was associated with oral tretinoin therapy. Marked exfoliation of the skin of the palms and soles also occurred (Akiyama et al, 1992; Sakakibara et al, 1993; Suzumiya et al, 1994).
b) Approximately 77% of patients experienced skin/mucous membrane dryness, which is a typical retinoid toxic effect and may be observed in patients who ingest high doses of vitamin A (Prod Info VESANOID(R) oral capsules, 2004).
D) SKIN FINDING 1) WITH THERAPEUTIC USE a) CASE REPORT: A 21-year-old woman applied 0.05% tretinoin gel four times daily to treat facial acne. The medication was discontinued due to redness, blistering, and crusting to the areas that were applied with gel. After waiting two weeks for the reaction to subside, the patient noticed superficial 1-cm scars in each nasolabial fold (Hogan, 1987).
E) ALOPECIA 1) WITH THERAPEUTIC USE a) Alopecia was reported by 14% of patients receiving oral tretinoin therapy (Prod Info VESANOID(R) oral capsules, 2004).
F) FLUSHING 1) WITH THERAPEUTIC USE a) Facial flushing was reported in 13 patients following therapeutic oral administration of 9-cis retinoic acid. The facial flushing commonly occurred 2 to 4 hours after drug ingestion, at higher dose levels, and was associated with the occurrence of headaches (Miller et al, 1996).
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Musculoskeletal |
3.15.1) SUMMARY
A) Bone pain and myositis are associated with oral therapeutic use of tretinoin. Arthralgias and myalgias have been reported following tretinoin and 9-cis retinoic acid therapy.
3.15.2) CLINICAL EFFECTS
A) BONE PAIN 1) WITH THERAPEUTIC USE a) Moderate bone pain occurred following the use of oral tretinoin (Akiyama et al, 1992; Mahmoud et al, 1993).
b) Approximately 77% of patients experienced bone pain as a result of oral tretinoin therapy for acute promyelocytic leukemia (Prod Info VESANOID(R) oral capsules, 2004).
B) MYOSITIS 1) WITH THERAPEUTIC USE a) CASE REPORT: A 33-year-old male developed a high fever and multiple painful nodules on both legs approximately 3 weeks after beginning oral tretinoin therapy, 45 mg/m(2) of body surface area/day. A muscle biopsy showed focal necrosis of the muscle fibers, edema, and inflammatory cell infiltration, all indicative of acute myositis. Discontinuation of the tretinoin and initiation of intravenous dexamethasone therapy, 10 mg twice daily, caused the gradual resolution of the nodules (Miranda et al, 1994).
C) MUSCLE PAIN 1) WITH THERAPEUTIC USE a) INCIDENCE/CHILDREN: Six of 9 children given oral tretinoin, 45 mg/m(2) of body surface area, to treat acute promyelocytic leukemia, complained of moderate bone pain and myalgias. Analgesia was achieved with paracetamol and codeine or morphine sulfate (Mahmoud et al, 1993).
b) INCIDENCE: Approximately 14% of patients complained of myalgias following oral tretinoin therapy (Prod Info VESANOID(R) oral capsules, 2004).
c) INCIDENCE: In a study evaluating oral tretinoin in patients with myelodysplastic syndrome, 7 of 39 patients experienced arthralgias. It was the dose-limiting toxicity in only one patient at the 250 mg/m(2) of body surface area/day dose level (Kurzrock et al, 1993).
d) 9-CIS RETINOIC ACID: During clinical trials for 9-cis retinoic acid, 12 of 34 patients developed arthralgias and myalgias shortly after initiation of treatment. Two of the 12 patients required narcotic analgesics (Miller et al, 1996).
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Immunologic |
3.19.2) CLINICAL EFFECTS
A) ACUTE ALLERGIC REACTION 1) WITH THERAPEUTIC USE a) A case of hyperhistaminemia (histamine levels were 100 times greater than normal) and a marked increase in basophils following oral tretinoin, 80 mg daily, was reported. The patient's increased histamine level contributed to the development of gastric and duodenal ulcers. The ulcers gradually healed after complete hematologic remission (Koike et al, 1992).
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Summary Of Exposure |
A) USES: Tretinoin (All-trans-retinoic acid) and related compounds are forms of vitamin A. Tretinoin topical formulation is used for the treatment of acne vulgaris, mottled hyperpigmentation, and tactile roughness of facial skin. Tretinoin oral capsule is used to induce the remission of acute promyelocytic leukemia (APL). Acitretin is used orally for the treatment of severe refractory psoriasis in adults. Refer to "ISOTRETINOIN" management for specific information about isotretinoin.
B) PHARMACOLOGY: The mechanisms of action are not fully elucidated. Tretinoins can affect nuclear transcription in epithelial cells and fibroblasts, and protein synthesis. Tretinoin induces cytodifferentiation and decreased proliferation of APL cells. For acne, it may decrease cohesiveness of follicular epithelial cells and decreased microcomedo formation.
C) TOXICOLOGY: In overdose, it can affect multiple organ systems and can be similar to symptoms of hypervitaminosis A.
D) EPIDEMIOLOGY: Overdose is uncommon and most cases develop only minor symptoms. Severe toxicity is very rare and deaths have not been reported.
E) WITH THERAPEUTIC USE
1) Common adverse effects with therapeutic dosing include chest discomfort, edema, rash, skin irritation, weight gain, abdominal pain, diarrhea, nausea and vomiting, increased liver enzymes, bone pain, headache, dizziness, dyspnea, fever, and malaise. Pseudotumor cerebri, hypercalcemia, hyperlipidemia and pancreatitis have been reported. The retinoic acid syndrome can occur after oral administration of tretinoin. Manifestations can include fever, dyspnea, weight gain, pulmonary infiltrates, pleural or pericardial effusion, leukocytosis, tachycardia, and hypotension. Topical application causes drying of skin. Tretinoin is a human teratogen.
F) WITH POISONING/EXPOSURE
1) MILD TO MODERATE TOXICITY: Abdominal pain, vomiting, diarrhea, and general malaise may occur.
2) SEVERE TOXICITY: Severe toxicity includes hepatotoxicity and hepatic failure, renal insufficiency and acute renal failure, hypotension, and acute lung injury.
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Vital Signs |
3.3.1) SUMMARY
A) Fever and dyspnea occur frequently as components of the "retinoic acid syndrome" in patients with acute promyelocytic leukemia, and may be accompanied by tachycardia and hypotension.
B) Increased respiratory rate and hypertension are less frequent occurrences.
3.3.2) RESPIRATIONS
A) WITH THERAPEUTIC USE 1) DYSPNEA, usually referred to as part of the "retinoic acid syndrome", is a frequent occurrence with therapeutic use of tretinoin in patients with acute promyelocytic leukemia (Frankel et al, 1992; Runde et al, 1992). a) Six patients, involved in clinical trials for 9-CIS retinoic acid, developed worsening dyspnea during treatment. The dyspnea resolved following discontinuation of the drug (Miller et al, 1996).
2) INCREASED RESPIRATORY RATE was reported in a 32-year-old woman following a second dose of oral tretinoin, 45 mg/m(2) of body surface area, to treat acute promyelocytic leukemia. The patient's chest x-ray revealed diffuse pulmonary infiltrates (Mahendra et al, 1994). 3.3.3) TEMPERATURE
A) WITH THERAPEUTIC USE 1) FEVER is a frequent occurrence and is usually referred to as a component of the "retinoic acid syndrome" in patients with acute promyelocytic leukemia (Shimoni et al, 1995; Mahendra et al, 1994; Miranda et al, 1994) Yokokura et al, 1994; (Chanarin et al, 1993; Roberts et al, 1992; Van der Hem & Ossenkoppele, 1992). a) Approximately 83% of patients have reported experiencing fever following oral tretinoin therapy for acute promyelocytic leukemia (Prod Info VESANOID(R) oral capsules, 2004).
b) CASE SERIES: In a case series report, 9 of 35 patients with acute promyelocytic leukemia treated with oral tretinoin, 45 mg/m(2) of body surface area/day, developed a syndrome consisting primarily of fever and respiratory distress. The onset of this symptom complex occurred 2 to 21 days after starting treatment (Frankel et al, 1992).
c) CASE REPORT: Fever, inflammatory skin nodules, malaise, and neutrophilia developed in a 50-year-old woman following oral tretinoin therapy, 80 mg daily. The symptoms, which are characteristics of a disorder called Sweet's syndrome, resolved following treatment with intravenous methylprednisolone, 1 g daily for 3 days (Cox & O'Brien, 1994).
d) CASE REPORT: Fever and total body flushing developed in a 36-year-old male 12 to 25 days after beginning oral tretinoin therapy (Koike et al, 1992).
3.3.4) BLOOD PRESSURE
A) WITH THERAPEUTIC USE 1) HYPOTENSION has been reported following therapeutic use of oral tretinoin in patients with acute promyelocytic leukemia (Mahendra et al, 1994; Chanarin et al, 1993; Frankel et al, 1992; Koike et al, 1992). a) INCIDENCE: In clinical trials, approximately 14% of patients with acute promyelocytic leukemia developed hypotension (Prod Info VESANOID(R) oral capsules, 2004).
2) HYPERTENSION occurs less frequently and has been reported in 11% of patients receiving therapy for acute promyelocytic leukemia (Prod Info VESANOID(R) oral capsules, 2004). 3.3.5) PULSE
A) WITH THERAPEUTIC USE 1) TACHYCARDIA has been reported following therapeutic doses. a) CASE REPORT: A pulse rate of 100 beats/min occurred in a 22-year-old woman following oral tretinoin therapy to treat acute promyelocytic leukemia (Chanarin et al, 1993).
b) CASE REPORT: Tachycardia was reported in a 32-year-old woman after a second dose of oral tretinoin, 45 mg/m(2) of body surface area (Mahendra et al, 1994).
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Heent |
3.4.1) SUMMARY
A) Papilledema (as a component of pseudotumor cerebri), irreversible hearing loss, lip and eye dryness, and cheilitis may occur in association with therapeutic tretinoin administration.
3.4.3) EYES
A) WITH THERAPEUTIC USE 1) PAPILLEDEMA is a common occurrence as a component of pseudotumor cerebri and may occur with or without sixth nerve palsies (Delaney & Narayanaswamy, 1990; Smith et al, 1992; Mahmoud et al, 1993; Smith-Whitley & Lange, 1993; Schmitt et al, 1994). 2) VISION CHANGES: Intermittent loss of vision has been reported in patients with pseudotumor cerebri associated with therapeutic tretinoin use (Mahmoud et al, 1993). a) Visual disturbances have been reported in 17% of patients with acute promyelocytic leukemia (Prod Info VESANOID(R) oral capsules, 2004).
b) Altered visual acuity and visual field defects have occurred in 6% and 3% of patients with acute promyelocytic leukemia, respectively (Prod Info VESANOID(R) oral capsules, 2004).
3) CORNEAL CALCIFICATION: Two cases of corneal calcification were reported following topical administration of tretinoin to treat dry eye syndrome. In the first case report, there was no noticeable improvement of the calcification following discontinuation of the tretinoin. In the second case report, the corneal calcification disappeared two months after the withdrawal of the tretinoin (Avisar et al, 1988). 4) ECTROPION: Two cases of bilateral ectropion developed during chronic topical administration of tretinoin. The ectropion resolved following discontinuation of the tretinoin (Brodell et al, 1992). 5) EYE DRYNESS has been reported following therapeutic doses. a) CASE SERIES: Dry eye sensation occurred in 3 of 17 children following oral tretinoin therapy for acute promyelocytic leukemia (Smith et al, 1992).
b) CASE SERIES: Dry eyes were experienced by 50% or more of patients with myelodysplastic syndrome treated with oral tretinoin, in doses of greater than 50 mg/m(2) of body surface area/day. One patient receiving 200 mg/m(2) of body surface area/day developed severe eye dryness, accompanied by conjunctivitis and periorbital edema. Symptoms resolved following discontinuation of the tretinoin (Kurzrock et al, 1993).
3.4.4) EARS
A) WITH THERAPEUTIC USE 1) EARACHE has been reported following therapeutic doses. a) In patients with acute promyelocytic leukemia, 23% experienced earaches or fullness of the ears (Prod Info VESANOID(R) oral capsules, 2004).
b) A "stuffed ears" sensation occurred in five patients with myelodysplastic syndrome 5 to 50 days after initiation of oral tretinoin therapy at doses greater than 150 mg/m(2) of body surface area/day (Kurzrock et al, 1993).
2) HEARING LOSS has been reported following therapeutic doses. a) With oral administration of tretinoin, approximately 6% of patients have reported some type of hearing loss, and 1% of patients experienced irreversible hearing loss (Prod Info VESANOID(R) oral capsules, 2004).
b) In 3 out of 5 patients, with "stuffed ears" sensation, a significant decrease in hearing occurred several days later. An audiogram, performed on 2 of the 3 patients, showed irreversible sensorineural hearing loss. No baseline audiograms were available (Kurzrock et al, 1993).
3.4.5) NOSE
A) WITH THERAPEUTIC USE 1) EPISTAXIS occurred in 3 of 17 children following therapeutic use (Smith et al, 1992).
3.4.6) THROAT
A) WITH THERAPEUTIC USE 1) GINGIVAL HYPERPLASIA has been reported. a) CASE REPORT: Gingival hyperplasia and hyperleukocytosis developed in an 8-year-old female with acute promyelocytic leukemia, seven days after beginning oral tretinoin therapy, 45 mg/m(2) of body surface area/day. Gingival biopsy showed heavy infiltration by maturing granulocytes and areas of necrosis. The patient was treated with hydrocortisone and cytarabine. When the WBC decreased, the gingival hyperplasia resolved (Ruiz-Arguelles et al, 1995).
2) STOMATITIS has been reported. a) CASE REPORT: A 14-year-old female complained of lip dryness and stomatitis, along with hypercalcemia, headache, nausea, and fatigue, during 1 to 3 weeks after beginning oral tretinoin therapy, 70 mg/day (Sakakibara et al, 1993).
3) CHEILITIS may occur after therapeutic doses. a) CASE SERIES: Cheilitis occurred in 4 of 9 children who received oral tretinoin, 45 mg/m(2) of body surface area/day, to treat acute promyelocytic leukemia (Mahmoud et al, 1993).
b) CASE SERIES: Ten of 17 children developed cheilitis during an evaluation of oral tretinoin in pediatric patients with cancer (Smith et al, 1992).
c) Cheilitis occurred in patients receiving oral tretinoin, 100 mg/m(2) of body surface area/day or more. Generally, the symptoms disappeared following discontinuation of the tretinoin (Kurzrock et al, 1993).
4) LIP DRYNESS has been reported in conjunction with hypercalcemia following oral tretinoin therapy (Akiyama et al, 1992; Sakakibara et al, 1993; Suzumiya et al, 1994). |
Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) TACHYARRHYTHMIA 1) WITH THERAPEUTIC USE a) CASE REPORT: Tachycardia was reported in a 22-year-old woman following oral tretinoin therapy to treat acute promyelocytic leukemia (Chanarin et al, 1993).
b) CASE REPORT: A 32-year-old woman became tachycardic after a second dose of oral tretinoin, 45 mg/m(2) of body surface area (Mahendra et al, 1994).
c) CASE REPORT: Tachycardia and shock developed in a 36-year-old male 19 days after initiating oral tretinoin therapy, 80 mg/day (Koike et al, 1992).
d) Arrhythmias have been reported in 23% of patients with acute promyelocytic leukemia following therapeutic use of oral tretinoin (Prod Info VESANOID(R) oral capsules, 2004).
B) HYPOTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) Hypotension has occurred following therapeutic use of oral tretinoin (Perea et al, 2000; Mahendra et al, 1994; Chanarin et al, 1993; Frankel et al, 1992; Koike et al, 1992).
b) Approximately 14% of patients, involved in clinical trials of oral tretinoin for acute promyelocytic leukemia, have developed hypotension (Prod Info VESANOID(R) oral capsules, 2004).
C) HYPERTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) Hypertension is a less common adverse effect, occurring in 11% of patients (Prod Info VESANOID(R) oral capsules, 2004).
D) PERICARDIAL EFFUSION 1) WITH THERAPEUTIC USE a) In a case series, one patient experienced chest pain typical of pericarditis. An echocardiography showed pericardial effusion (Frankel et al, 1992).
E) MYOCARDIAL INFARCTION 1) WITH THERAPEUTIC USE a) Approximately 6% of patients with acute promyelocytic leukemia developed cardiac failure; 3% of patients experienced miscellaneous cardiac effects (eg, myocardial infarction, enlarged heart, heart murmur, ischemia, myocarditis, pericarditis) associated with oral tretinoin use (Prod Info VESANOID(R) oral capsules, 2004).
b) CASE REPORT: A patient, with a long history of coronary artery disease, suffered a myocardial infarction during a RBC transfusion following oral tretinoin, 150 mg/m(2) of body surface area/day. The patient died 21 days after initiation of tretinoin therapy (Kurzrock et al, 1993).
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Respiratory |
3.6.1) SUMMARY
A) Respiratory distress, including dyspnea, pulmonary infiltrates, and pleural effusions, commonly occurs and is usually classified as a component of the "retinoic acid syndrome". Death may occur due to respiratory failure.
B) Pulmonary embolism has been reported following therapeutic use.
3.6.2) CLINICAL EFFECTS
A) DYSPNEA 1) WITH THERAPEUTIC USE a) Respiratory distress, usually referred to as a component of the "retinoic acid syndrome" in patients with acute promyelocytic leukemia, commonly occurs with therapeutic oral tretinoin administration and may include dyspnea, interstitial infiltrates, and pleural effusion. Discontinuation of the tretinoin and treatment with dexamethasone may help resolve these effects (Shimoni et al, 1995; Miranda et al, 1994) Yokokura et al, 1994; (Chanarin et al, 1993; Roberts et al, 1992; Van der Hem & Ossenkoppele, 1992). b) Approximately 60% of patients reported experiencing dyspnea. Pleural effusion was observed in 20% of patients and pulmonary infiltration was observed in 6% of patients (Prod Info VESANOID(R) oral capsules, 2004). c) CASE SERIES: In a case series, 9 of 35 patients, treated with oral tretinoin, 45 mg/m(2) of body surface area/day, developed a symptom complex primarily characterized by fever and dyspnea. Interstitial infiltrates and pleural effusions were detected in chest radiographs of all cases (Frankel et al, 1992). 1) Post-mortem examination of two patients, involved in the series, showed extensive pulmonary interstitial infiltration with maturing myeloid cells.
d) CASE REPORT: A 4-year-old female developed acute respiratory distress and hypoxia 30 days after beginning oral tretinoin therapy, 45 mg/m(2) of body surface area/day, for treatment of acute promyelocytic leukemia. Chest radiographs showed interstitial infiltrates. Twenty-four hours later, despite supportive care, the patient died of respiratory failure (Smith-Whitley & Lange, 1993). e) CASE REPORT: A 32-year-old woman developed tachycardia, hypotension, increased respiratory rate, and poor urine output following the second oral dose of tretinoin, 45 mg/m(2) of body surface area. Her chest x-ray showed diffuse pulmonary infiltrates throughout her lungs. The patient deteriorated rapidly and died of respiratory and renal failure, despite receiving conventional chemotherapy and dexamethasone (Mahendra et al, 1994). f) 9-CIS RETINOIC ACID: Worsening dyspnea developed in six patients involved in clinical trials for 9-cis retinoic acid. The dyspnea resolved upon discontinuation of the drug (Miller et al, 1996). B) PULMONARY EMBOLISM 1) WITH THERAPEUTIC USE a) CASE REPORT: A 29-year-old male developed dyspnea and acute venous thrombosis seven days after beginning therapy with oral tretinoin for acute promyelocytic leukemia. Clinical examination and electrocardiogram, as well as perfusion and ventilation scintigraphy of the lungs, confirmed the presence of pulmonary embolism. The embolism and the thrombosis resolved following heparin therapy (Runde et al, 1992).
b) CASE REPORT: A 47-year-old woman with acute promyelocytic leukemia developed respiratory distress, hypoxemia, and right upper-quadrant pain three days after initiating oral tretinoin therapy, 45 mg/m(2) of body surface area/day. A pulmonary angiogram confirmed the presence of pulmonary emboli. Despite treatment with heparin, the patient died 3 days later due to progressive respiratory, renal, and hepatic failure secondary to extensive thromboses (Brouns et al, 1994).
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Neurologic |
3.7.1) SUMMARY
A) Pseudotumor cerebri, primarily characterized by headaches, intracranial hypertension, and papilledema, may occur following therapeutic use of tretinoin.
B) Fatigue, malaise, anxiety, insomnia, depression, agitation, and confusion have been reported.
C) Headaches, without being classified as pseudotumor cerebri, have been reported following therapeutic administration of 9-cis retinoic acid.
3.7.2) CLINICAL EFFECTS
A) BENIGN INTRACRANIAL HYPERTENSION 1) WITH THERAPEUTIC USE a) Pseudotumor cerebri, consisting of severe headaches, intracranial hypertension, retinal hemorrhages, and papilledema with or without sixth nerve palsies, may occur following therapeutic use of oral tretinoin or acitretin (Prod Info Soriatane(R), 1997; (Kentos et al, 1997; Schmitt et al, 1994; Mahmoud et al, 1993; Smith-Whitley & Lange, 1993). b) Approximately 85% of patients with acute promyelocytic leukemia have reported headaches and 9% of patients have reported intracranial hypertension following oral tretinoin therapy (Prod Info VESANOID(R) oral capsules, 2004). c) CASE REPORT/TOPICAL USE: A 29-year-old woman presented with a 10-day history of severe headaches and papilledema. The patient had been ingesting minocycline 250 milligrams twice daily, administering tretinoin ointment for 6 months for the treatment of acne, and, ten days prior to admission, intermittently ingesting chicken liver as a treatment for her skin condition. Physical exam showed bilateral papilledema and a diplopia with right sixth nerve paralysis. A spinal tap showed an elevated CSF pressure of 410 mm Hg. 1) The patient's headache resolved and the spinal fluid showed a pressure of 280 mm Hg ten days after discontinuing the medications and following treatment with furosemide and acetazolamide.
2) Minocycline has been known to cause pseudotumor cerebri and chicken livers contain vitamin A. It is possible that the signs and symptoms were due to an additive effect of minocycline and both sources of vitamin A (Delaney & Narayanaswamy, 1990).
d) CASE SERIES: A study, evaluating oral tretinoin in pediatric patients with cancer, determined that the dose-limiting toxicity at the 80 mg/m(2) of body surface area/day dose level was pseudotumor cerebri. In this study, the signs and symptoms related to pseudotumor cerebri were reversible (Smith et al, 1992). 1) The four patients who had evidence of increased intracranial pressure during tretinoin treatment, two with accompanying clinical symptoms and two with only papilledema, were all less than 8 years old.
B) ALTERED MENTAL STATUS 1) WITH THERAPEUTIC USE a) Malaise, anxiety, insomnia, depression, confusion, and agitation have been reported in patients during clinical trials with oral tretinoin (Prod Info VESANOID(R) oral capsules, 2004).
b) CASE REPORT: A 14-year-old female experienced general fatigue several days after beginning oral tretinoin therapy, 70 mg/day. The patient was also diagnosed with hypercalcemia. The fatigue improved when serum calcium concentrations decreased and after the tretinoin was discontinued (Sakakibara et al, 1993).
c) CASE REPORT: Malaise, fever, inflammatory skin nodules, and neutrophilia developed in a 50-year-old woman following oral tretinoin therapy, 80 mg daily. The symptoms, characteristics of a disorder called Sweet's syndrome, resolved following treatment with intravenous methylprednisolone 1 gram daily for three days (Cox & O'Brien, 1994).
C) HEADACHE 1) WITH THERAPEUTIC USE a) Twenty-one of 34 patients, given 9-CIS retinoic acid during clinical trials, developed mild to moderately severe headaches. The headaches were dose- limiting and resolved following discontinuation of the drug (Miller et al, 1996).
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Gastrointestinal |
3.8.1) SUMMARY
A) Nausea and vomiting, pancreatitis, hemorrhagic gastritis, and ulcers have been reported.
B) Pseudo-obstruction of the colon has occurred following induction therapy with tretinoin and chemotherapy.
3.8.2) CLINICAL EFFECTS
A) NAUSEA AND VOMITING 1) WITH THERAPEUTIC USE a) Nausea and vomiting were reported in 57% of patients following oral tretinoin therapy for acute promyelocytic leukemia (Prod Info VESANOID(R) oral capsules, 2004).
b) CASE REPORT: A 14-year-old female complained of nausea following treatment with oral tretinoin, 70 mg/day (Sakakibara et al, 1993).
c) Four patients experienced nausea with or without vomiting with oral tretinoin 50 mg/m(2) of body surface area/day or greater. The nausea usually appeared within the first few days of therapy and quickly subsided upon discontinuation of the tretinoin (Kurzrock et al, 1993).
2) WITH POISONING/EXPOSURE a) CASE REPORT (OVERDOSE): A 32-year-old male ingested 21 capsules of acitretin 25 mg (total dose ingested was 525 mg) and experienced vomiting several hours later with no other adverse effects reported (Prod Info SORIATANE(R) capsules, 2004).
B) DIARRHEA 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 31-year-old man with history of AIDS and acute promyelocytic leukemia (in remission) developed diarrhea, but was otherwise asymptomatic after ingesting a self-reported 1000 mg of tretinoin (100 10 mg-tablets). A tretinoin drug level was not obtained, but toxicology screening was negative for drugs of abuse (Su-Yin et al, 2009).
C) PANCREATITIS 1) WITH THERAPEUTIC USE a) CASE REPORT: A 44-year-old woman ingested 60 mg tretinoin daily to treat acute promyelocytic leukemia. Three weeks later, the patient's pancreatic enzymes and triglyceride levels were elevated. The pancreatic enzymes and triglyceride levels returned to normal following discontinuation of tretinoin (Izumi et al, 1994).
b) ACITRETIN: Fatal fulminant pancreatitis was reported in one patient following therapeutic administration of acitretin (Prod Info SORIATANE(R) capsules, 2004).
D) GASTRIC HEMORRHAGE 1) WITH THERAPEUTIC USE a) CASE REPORTS: Two cases of hemorrhagic gastritis occurred following oral administration of tretinoin to treat acute promyelocytic leukemia (Patterson et al, 1994). 1) The first case involved a 71-year-old woman receiving tretinoin, 70 mg/day, complaining of epigastric pain four days later. An endoscopy revealed hemorrhagic diffuse gastritis. The patient was treated with omeprazole for the duration of tretinoin therapy.
2) The second case involved a 49-year-old male ingesting tretinoin 90 mg/day and complaining of abdominal discomfort three days later. An endoscopy revealed hemorrhagic gastritis. Treatment with omeprazole, misoprostol, and sucralfate provided symptomatic relief. A repeat endoscopy, performed seven days later, showed complete resolution of the gastritis.
b) Approximately 30% of patients reported gastrointestinal hemorrhage and/or abdominal pain as a result of oral tretinoin therapy (Prod Info VESANOID(R) oral capsules, 2004). E) GASTRIC ULCER 1) WITH THERAPEUTIC USE a) CASE REPORT: A 36-year-old male began tretinoin, 80 mg/day, and developed hematemesis and melena 27 to 29 days later. A large gastric ulcer and two bleeding duodenal ulcers were detected by gastroscopy. The ulcers healed following hematologic remission. 1) The ulcers were secondary to the development of hyperhistaminemia that occurred in the patient approximately 10 days after beginning oral tretinoin therapy (Koike et al, 1992).
b) Approximately 3% of patients developed ulcers during clinical trials of oral tretinoin therapy (Prod Info VESANOID(R) oral capsules, 2004). F) SWOLLEN ABDOMEN 1) WITH THERAPEUTIC USE a) CASE REPORT: A 53-year-old woman with acute promyelocytic leukemia began oral tretinoin therapy, 45 mg/m(2) of body surface area/day, and developed abdominal pain and marked distension 24 days later. Plain radiographs of the abdomen showed massive gaseous distension of the large bowel without any fluid levels. The abdominal condition worsened and she died 10 days later. The abdominal symptoms were consistent with an acute colonic pseudo-obstruction, also called Ogilvie's syndrome (Delmer et al, 1995).
b) Abdominal distension was reported in 11% of patients with acute promyelocytic leukemia following oral tretinoin therapy (Prod Info VESANOID(R) oral capsules, 2004).
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Hepatic |
3.9.1) SUMMARY
A) Hepatotoxicity, including increased liver enzyme levels, hepatosplenomegaly, hepatitis, and hepatic failure, may occur in association with the therapeutic use of oral tretinoin or acitretin.
3.9.2) CLINICAL EFFECTS
A) LIVER DAMAGE 1) WITH THERAPEUTIC USE a) CASE REPORT: A 39-year-old male with acute promyelocytic leukemia developed cholestatic jaundice approximately 40 days following the initiation of oral tretinoin therapy, 60 mg/m(2) of body surface area. The liver enzyme levels and the serum bilirubin concentration progressively increased despite cessation of tretinoin. Eighteen days after the discontinuation, the patient's serum bilirubin concentration decreased to normal values (Shibata et al, 1994). b) In clinical trials with oral tretinoin for acute promyelocytic leukemia, 50% to 60% of patients experienced elevated liver function tests, 9% developed hepatosplenomegaly, and 3% developed hepatitis (Prod Info VESANOID(R) oral capsules, 2004). c) CASE SERIES: In a case series reported, several patients developed hyperbilirubinemia following oral tretinoin therapy. Three patients died of progressive pulmonary, renal, and hepatic failure (Frankel et al, 1992). d) In a study evaluating tretinoin in pediatric patients with cancer, transient elevations of serum transaminases were observed as the dose-limiting toxicity in one patient at the 60 mg/m(2) of body surface area/day dose level. The enzymes returned to baseline level within one week after discontinuation of the tretinoin (Smith et al, 1992). e) CASE REPORT: A 40-year-old male with acute promyelocytic leukemia, treated with all-trans-retinoic acid (ATRA) developed elevated liver enzyme levels and hepatomegaly after 21 days. Percutaneous liver biopsy showed intracellular cholestasis. ATRA was discontinued and, within 2 weeks, the patient's hepatic function normalized (Perea et al, 2000). f) ACITRETIN: In US clinical trials with oral acitretin for the treatment of severe psoriasis, 2 of the 525 patients developed clinical jaundice with elevated hepatic enzyme levels. Elevations of liver enzyme levels alone have occurred in approximately 1 in 3 patients treated with acitretin. Of the 525 patients in the US clinical trials, treatment was discontinued in 20 patients (3.8%) due to the elevated liver enzyme levels (Prod Info Soriatane(R), 1997). 1) Two of the 1289 patients involved in European clinical trials, with acitretin, developed toxic hepatitis, confirmed by liver biopsy. Cirrhosis was also suggested following a second biopsy in one of the two patients. One patient (n=63) in a Canadian clinical trial developed a three-fold increase in transaminases following therapeutic acitretin administration (Prod Info Soriatane(R), 1997).
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Genitourinary |
3.10.1) SUMMARY
A) Renal insufficiency, possibly developing into renal failure, may occur in tretinoin-treated patients.
B) Vaginal bleeding, associated with the topical application of tretinoin cream, was reported.
3.10.2) CLINICAL EFFECTS
A) ABNORMAL RENAL FUNCTION 1) WITH THERAPEUTIC USE a) Renal insufficiency was reported in 11% of patients using oral tretinoin therapeutically (Prod Info VESANOID(R) oral capsules, 2004).
b) CASE SERIES: Renal insufficiency occurred in 6 of 35 patients with acute promyelocytic leukemia treated with oral tretinoin, 45 mg/m(2) of body surface area/day (Frankel et al, 1992).
c) CASE REPORT: A 32-year-old woman developed poor urine output and an increase in creatinine to a maximum of 200 mmol/L after her second oral dose of tretinoin, 45 mg/m(2) of body surface area. Despite hemodialysis, the patient continued to deteriorate and died approximately 35 hours after the second dose of tretinoin (Mahendra et al, 1994).
d) CASE REPORT: A 47-year-old male developed an increase in BUN and serum creatinine 4 days after beginning oral tretinoin therapy, 80 mg/day. The patient recovered following diuretic administration (Yokokura et al, 1994).
e) CASE REPORT: Renal insufficiency and oliguria were reported in a 40-year-old male, with acute promyelocytic leukemia, following treatment with all-trans-retinoic acid (ATRA). The patient's renal function normalized within 2 weeks after discontinuation of ATRA therapy (Perea et al, 2000).
B) RENAL FAILURE SYNDROME 1) WITH THERAPEUTIC USE a) INCIDENCE: Approximately 3% of patients reported acute renal failure as a result of oral tretinoin therapy for acute promyelocytic leukemia (Prod Info VESANOID(R) oral capsules, 2004).
b) CASE REPORT: Progressive non-oliguric renal failure was diagnosed in a 66-year-old woman two weeks after initiating therapy with oral tretinoin, 45 mg/m(2) of body surface area twice daily. The patient also developed adult respiratory distress syndrome. The renal failure did not improve upon discontinuation of the tretinoin, therefore prompting regular hemodialysis. The patient died three weeks later due to multiple organ failure (Van der Hem & Ossenkoppele, 1992).
C) FINDING OF VAGINAL BLEEDING 1) WITH THERAPEUTIC USE a) CASE REPORT: Vaginal bleeding, along with pelvic and breast vascular congestion and nausea, occurred approximately five weeks after the beginning of nightly facial application of topical tretinoin cream. Three days after the patient stopped using the cream, the bleeding stopped. 1) Upon rechallenge with the tretinoin cream, the patient developed the same symptoms. Two days after the discontinuation of the medication, the symptoms resolved (Meurehg & Amelio, 1990).
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Reproductive |
3.20.1) SUMMARY
A) Oral tretinoin is classified as FDA pregnancy category D. The topical tretinoin, tretinoin in combination with clindamycin, and fluocinolone acetonide/hydroquinone/tretinoin are classified as FDA pregnancy category C. Acitretin is classified as FDA pregnancy category X. Fetal malformations have been reported in humans and animals following maternal use of tretinoin and acitretin during pregnancy, particularly in early stages of pregnancy with tretinoin exposure. It is not known whether oral or topical tretinoin is excreted into breast milk. Acitretin has been shown to be excreted in human breast milk.
3.20.2) TERATOGENICITY
A) LACK OF INFORMATION 1) FLUOCINOLONE ACETONIDE/HYDROQUINONE/TRETINOIN a) At the time of this review no data were available, no data were available to access the teratogenic potential of this agent. Tretinoin, a component of this drug, has been linked with embryofetal death, altered fetal growth, congenital malformations, and potential neurologic deficits when administered systemically. Although, human data have not confirmed an increased risk of teratogenic abnormalities with topical administration of tretinoin (Prod Info TRI-LUMA(R) topical cream, 2013).
B) EMBRYO/FETAL RISK 1) ACITRETIN a) Acitretin is a metabolite of etretinate, and both agents have been associated with major human fetal abnormalities, including meningomyelocele, meningoencephalocele, multiple synostoses, facial dysmorphia, syndactyly, absence of terminal phalanges, hip, ankle and forearm malformations, limb contractures, low set ears, microtia, high palate, small mouth, maxilla hypoplasia, decreased cranial volume, cardiovascular malformation and alterations of the skull and cervical vertebrae (Prod Info SORIATANE(R) oral capsules, 2015; Barbero et al, 2004). Acitretin has a shorter elimination half-life than etretinate; however, concurrent use of acitretin with ethanol may result in formation of etretinate, which has a very extended half-life and, thus, higher potential for teratogenic effects in women of childbearing age (Prod Info SORIATANE(R) oral capsules, 2015; Brindley, 1989; Warren & Khanderia, 1989).
b) Fetal abnormalities have been reported in pregnant women who were treated with etretinate, acitretin or both. In 238 of these cases, conception occurred after the last dose of etretinate, acitretin, or both. Approximately half of these cases had unknown fetal outcomes, including 62 terminated pregnancies and 14 spontaneous abortions. Of the 118 cases in which fetal outcome was known, 15 were abnormal, including cases of absent hand/wrist, clubfoot, GI malformation, hypocalcemia, hypotonia, limb malformation, neonatal apnea/anemia, neonatal ichthyosis, placental disorder/death, undescended testicle, and 5 were cases of premature birth. Of the 126 prospectively reported cases in which conception occurred following the last acitretin dose, 43 of the pregnancies were conceived between one and two years after the last dose. Three of the 43 cases reported abnormal outcomes of limb malformation, GI tract malformations and premature birth. Four cases occurred at least 2 years after the last dose and there were no reports of birth defects (Prod Info SORIATANE(R) oral capsules, 2015).
c) Fetal abnormalities were observed in 35 retrospectively reported cases in which conception occurred at least 1 year following treatment with etretinate, acitretin, or both. Birth defects were observed in 3 cases (heart malformations, Turner's Syndrome, and unspecified congenital malformations) and 4 cases (foot malformation, 2 cases of cardiac malformations, and unspecified neonatal and infancy disorder) where conception occurred between one and two years and 2 years or greater, respectively, following the last acitretin dose. Three cases of abnormal outcomes, including chromosome disorder, forearm aplasia, and stillbirth, were reported when conception occurred 2 or more years after the last etretinate dose (Prod Info SORIATANE(R) oral capsules, 2015).
d) After using oral acitretin 10 mg/day (0.18 mg/kg/day) from the beginning of pregnancy until the 10th gestational week, a 22-year-old with Darier disease delivered an infant with microcephaly, epicanthal folds, low nasal bridge, high palate, cup-shaped ears, anteverted nostrils, atrial septal defect, and bilateral sensorineural deafness. The infant was microcephalic and hypotonic and showed neurodevelopmental delay at 18 months of age (Barbero et al, 2004).
2) TRETINOIN a) Multiple congenital defects were associated with the maternal use of topical tretinoin 0.05% before conception and during the first trimester of pregnancy. The defects included supraumbilical exomphalos, an anterior diaphragmatic hernia, an inferior pericardial defect, coarctation of the aorta, dextroposition of the heart, absent or small ear canals, hypertelorism, dysplastic kidneys, CNS abnormalities, a hypoplastic left hand, and a right-side upper limb reduction defect (Lipson et al, 1993; Shapiro et al, 1997; Navarre-Belhassen et al, 1998; Colley et al, 1998; Selcen et al, 2000).
b) An ear malformation, consisting of a crumpled hypoplastic ear and atresia of the external auditory meatus on the right side, was reported in an infant following maternal use of tretinoin cream 0.05% prior to conception and during the first trimester of pregnancy (Camera & Pregliasco, 1992).
C) LACK OF EFFECT 1) TRETINOIN a) TOPICAL 1) Topical tretinoin was not associated with an increased risk for major congenital disorders in a study evaluating the risk of birth defects in women using topical tretinoin during the first trimester of pregnancy. The prevalence of major anomalies among babies born to the exposed women (n=212) was 1.9% and among babies born to the non-exposed women (n=427) was 2.6% (Jick et al, 1993). Another study confirmed these results (Shapiro et al, 1997).
D) ANIMAL STUDIES 1) TRETINOIN a) ORAL 1) RATS, MICE, HAMSTERS, MONKEYS: Teratogenicity has been demonstrated in rats, mice, rabbits, hamsters, and primates treated with oral tretinoin. In rats treated with oral tretinoin (1000 times the average recommended human topical dose), teratogenicity and fetotoxicity were observed; however, the teratogenic dose varied among different strains of rats. In cynomolgus monkeys, fetal malformations were noted at oral tretinoin doses of 10 mg/kg/day or greater and increased skeletal variations were observed at all doses. No malformations were observed at 5 mg/kg/day (1000 times the average recommended human topical dose) (Prod Info AVITA(R) topical cream, 0.025%, 2006).
2) MICE, RATS, HAMSTERS, MONKEYS: Gross external, soft tissue, and skeletal alterations were observed at oral tretinoin doses greater than 0.7 mg/kg/day in mice, 2 mg/kg/day in rats, 7 mg/kg/day in hamsters, and at a dose of 10 mg/kg/day in pigtail monkeys (about 1/20, 1/4, 1/2, and 4 times, respectively, the human dose on a mg/m(2) basis) (Prod Info VESANOID(R) oral capsules, 2004).
3) MICE: Limb defects and cleft palate in fetal mice were associated with the maternal administration of tretinoin, orally and intraperitoneally, during the early stages of pregnancy (Scott et al, 1994; Abbott et al, 1989).
4) MICE: Spina bifida occurred in 31 of 39 fetal mice (79%) exposed to high maternal doses of tretinoin administered during the early stages of pregnancy (Alles & Sulik, 1990).
b) TOPICAL 1) RATS: No teratogenic effects were observed in rats treated with 0.025% tretinoin gel during gestation days 6 through 15 at doses of 2 mL/kg. Craniofacial and heart abnormalities were observed at 16 times the recommended clinical dose based on body surface area, although no systemic levels of tretinoin were found (Prod Info VELTIN(TM) topical gel, 2010).
2) RATS, RABBITS: Topical tretinoin has been shown to be teratogenic in rats at doses greater than 1 mg/kg/day, about 200 times the recommended human topical dose (shortened or kinked tail), in rats exposed to 10 mg/kg/day (humerus: short, 13%; bent, 6%; parietal incompletely ossified, 14%), in rabbits with doses of about 91 times the recommended human dose for topical 0.1% cream (cleft palate and hydrocephaly), and in New Zealand rabbits treated with 80 times the recommended human topical dose (domed head and hydrocephaly). Subcutaneous tretinoin was teratogenic at 2 mg/kg/day (approximately 400 times the human topical dose of 0.025% cream), but not at 1 mg/kg/day (approximately 200 times the human dose) (Prod Info AVITA(R) topical cream, 0.025%, 2006; Prod Info RETIN-A(R) topical cream, gel, liquid, 2002).
3) RATS, RABBITS: There have been several well-controlled animal studies in which teratogenicity has not been demonstrated when rats and rabbits were treated with topical tretinoin at doses 100 and 200 times, respectively, the recommended human topical dose (Prod Info AVITA(R) topical cream, 0.025%, 2006).
c) ACITRETIN 1) During animal studies, acitretin was teratogenic and embryotoxic with oral acitretin doses approximately 0.2, 0.3, and 3 times the maximum recommended therapeutic dose, based on surface area. No teratogenic effects were observed in a study of male animals that were treated with acitretin prior to and during mating with untreated female rats (Prod Info SORIATANE(R) oral capsules, 2015).
2) FLUOCINOLONE ACETONIDE/HYDROQUINONE/TRETINOIN a) RABBITS, RATS: Fetal deaths and decreased fetal weights were noted in the offspring of pregnant rabbits following topical application of fluocinolone acetonide/hydroquinone/tretinoin cream in a clinical study. In pregnant rats treated topically during organogenesis, teratogenic effects consistent with tretinoin administration included cleft palate, protruding tongue, open eyes, retinal folding or dysplasia, and umbilical hernia in exposed offspring. Topical therapy with a 10-fold dilution of fluocinolone acetonide/hydroquinone/tretinoin cream in pregnant rats showed increases in stillborn pups, lower pup body weights, and delayed preputial separations. Postnatal behavioral effects consistent with gestational exposure to retinoic acids included increased overall activity in some litters on day 22 and in all exposed litters at 5 weeks. Clinical dosing comparisons are not possible in animal studies using dermal application (Prod Info TRI-LUMA(R) topical cream, 2013).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) ACITRETIN a) The manufacturer has classified acitretin as FDA pregnancy category X (Prod Info SORIATANE(R) oral capsules, 2015).
2) TRETINOIN a) The manufacturer has classified oral tretinoin as FDA pregnancy category D (Prod Info VESANOID(R) oral capsules, 2004)
b) The manufacturer has classified topical tretinoin as FDA pregnancy category C (Prod Info AVITA(R) topical cream, 0.025%, 2006; Prod Info RETIN-A(R) topical cream, gel, liquid, 2002).
c) CLINDAMYCIN AND TRETINOIN: The manufacturer has classified topical tretinoin in combination with clindamycin as FDA pregnancy category C (Prod Info VELTIN(TM) topical gel, 2010).
3) FLUOCINOLONE ACETONIDE/HYDROQUINONE/TRETINOIN a) The manufacturer has classified topical fluocinolone acetonide/hydroquinone/tretinoin as FDA pregnancy category C (Prod Info TRI-LUMA(R) topical cream, 2013).
B) CONTRACEPTION 1) ACITRETIN a) Patients must simultaneously use 2 adequate forms of contraception for at least one month prior to treatment, during treatment, and for at least 3 years after discontinuation. Unless absolute abstinence is the chosen method of contraception or the patient has undergone a hysterectomy or is postmenopausal, at least one contraceptive method must be a primary form (ie, tubal ligation, vasectomy, intrauterine devices, birth control pills/injections/implants/insertions) (Prod Info SORIATANE(R) oral capsules, 2015).
C) PREGNANCY TESTING 1) ACITRETIN a) Pregnancy must be excluded prior to initiating treatment. At least 2 negative urine or serum pregnancy tests with a minimum sensitivity of 25 milli-international units/mL are required. The second pregnancy test must be performed during the first 5 days of menstrual period that precedes treatment initiation. If a patient has amenorrhea, perform the second test at least 11 days after unprotected sex. Treatment must be initiated within 7 days of the second negative pregnancy test (Prod Info SORIATANE(R) oral capsules, 2015).
b) Repeat pregnancy testing (minimum sensitivity of 25 milli-international units/mL) every month during treatment and every 3 months after discontinuation of therapy for at least 3 years (Prod Info SORIATANE(R) oral capsules, 2015).
D) FLUOCINOLONE ACETONIDE/HYDROQUINONE/TRETINOIN 1) Thirteen women became pregnant during treatment with topical fluocinolone acetonide/hydroquinone/tretinoin cream in clinical trials. Outcomes included births of 3 apparently healthy babies, 1 pregnancy termination, and 1 miscarriage. The remaining outcomes were unknown. Epidemiologic studies of topical tretinoin do not show an increased incidence of birth defects, though neurologic or cognitive impairments may not be detected (Prod Info TRI-LUMA(R) topical cream, 2013).
E) TRETINOIN 1) Acitretin is contraindicated during pregnancy as numerous cases of major acitretin-related fetal abnormalities have been reported. If pregnancy occurs during use, the patient should be advised of possible consequences to the fetus and of the risk of miscarriage. Acitretin should not be used during pregnancy and in women of childbearing potential unless a number of conditions are met. The manufacturer recommends two forms of effective contraception be used simultaneously during acitretin therapy and for 3 years following completion of therapy; exceptions may be made for women with a hysterectomy or choosing abstinence. In addition, female patients of childbearing age are required to have 2 negative pregnancy tests prior to starting acitretin and a repeat pregnancy test monthly during therapy and every three months for at least 3 years following completion of acitretin therapy. Treatment with acitretin should be discontinued if a positive pregnancy test occurs. In order for acitretin to be adequately eliminated, ethanol must not be ingested during use or for 2 months after cessation of acitretin treatment. Acitretin is approved for marketing only under a special restricted distribution program, called the Do Your P.A.R.T (Pregnancy Prevention Actively Required During and After Treatment), approved by the Food and Drug Administration. Program materials can be requested by calling 1-888-784-3335 or on www.soriatane.com/doyour-part-Program.html. Provide male and female patients with a medication guide for acitretin each time the drug is dispensed, as required by law. Acitretin is a metabolite of etretinate and maternal use of both drugs has resulted in major human fetal abnormalities. Paternal use of acitretin has resulted in spontaneous and induced abortions. If pregnancy occurs during use, the patient should report the pregnancy to the manufacturer at 1-888-784-3335 or the to Food and Drug Administration (FDA) MedWatch program at 1-800-FDA-1088 (Prod Info SORIATANE(R) oral capsules, 2014).
F) ANIMAL STUDIES 1) ACITRETIN a) During animal studies, acitretin doses, approximately one-half the maximum recommended therapeutic dose, resulted in slightly decreased pup survival and delayed incisor eruption; however, those treated with 1 mg/kg/day demonstrated no treatment-related adverse effects (Prod Info SORIATANE(R) oral capsules, 2015).
2) TRETINOIN a) MONKEYS: In cynomolgus monkeys treated with oral tretinoin, dose-related increased embryolethality and abortion were reported. Similar results have been reported in pigtail macaques treated with oral tretinoin (Prod Info AVITA(R) topical cream, 0.025%, 2006; Prod Info RETIN-A(R) topical cream, gel, liquid, 2002).
b) MICE, RATS, HAMSTERS, RABBITS, MONKEYS: In mice, rats, hamsters, rabbits and pigtail monkeys treated with oral tretinoin, fetal resorptions and a decrease in live fetuses were reported (Prod Info VESANOID(R) oral capsules, 2004).
c) RABBITS: Fetotoxicity was demonstrated in rabbits treated with topical tretinoin in doses 100 times the recommended topical human dose and in rats treated with oral tretinoin in doses 500 times the recommended human topical dose (Prod Info AVITA(R) topical cream, 0.025%, 2006).
d) RABBITS, MICE, RATS: Acitretin was embryotoxic in pregnant rabbits, mice and rats treated with oral acitretin doses of 0.6 mg/kg, 3 mg/kg, and 15 mg/kg, respectively (approximately 0.2, 0.3, and 3 times the maximum recommended therapeutic dose, based on surface area) (Prod Info SORIATANE(R) oral capsules, 2014).
3) FLUOCINOLONE ACETONIDE/HYDROQUINONE/TRETINOIN a) RABBITS, RATS: Fetal deaths and decreased fetal weights were noted in the offspring of pregnant rabbits following topical application of fluocinolone acetonide/hydroquinone/tretinoin cream in a clinical study. Topical therapy with a 10-fold dilution of fluocinolone acetonide/hydroquinone/tretinoin cream in pregnant rats showed increases in stillborn pups, lower pup body weights, and delayed preputial separations. Postnatal behavioral effects consistent with gestational exposure to retinoic acids included increased overall activity in some litters on day 22 and in all exposed litters at 5 weeks. Clinical dosing comparisons are not possible in animal studies using dermal application (Prod Info TRI-LUMA(R) topical cream, 2013).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) LACK OF INFORMATION 1) FLUOCINOLONE ACETONIDE/HYDROQUINONE/TRETINOIN a) Corticosteroids are excreted in human milk when administered systemically. It is not known if fluocinolone acetonide/hydroquinone/tretinoin is present in human milk following topical therapy, and the potential for adverse effects in the nursing infant from exposure to this drug is unknown. Until additional data are available, use caution with its use in women who are nursing. Avoid contact of fluocinolone acetonide/hydroquinone/tretinoin with the nursing infant (Prod Info TRI-LUMA(R) topical cream, 2013).
B) BREAST MILK 1) TRETINOIN a) Although there are no data available regarding the excretion of oral or topical tretinoin in breast milk, it is recommended that maternal use be discontinued due to potential serious adverse reactions in the nursing infant (Prod Info VESANOID(R) oral capsules, 2004; Prod Info AVITA(R) topical cream, 0.025%, 2006). Exercise caution when giving topical clindamycin/tretinoin gel to a nursing woman (Prod Info VELTIN(TM) topical gel, 2010).
b) TOPICAL CLINDAMYCIN/TRETINOIN: Orally and parenterally administered clindamycin has appeared in human milk. It is recommended that clindamycin use or nursing be discontinued due to potentially serious adverse reactions in the nursing infant (Prod Info VELTIN(TM) topical gel, 2010).
2) ACITRETIN a) Lactating mothers should not receive acitretin prior to or during nursing because of the potential for serious adverse reactions in nursing infants. In a prospective case report, acitretin was detected in human milk (Prod Info SORIATANE(R) oral capsules, 2015).
b) Using samples derived from one woman, the transfer of acitretin into human breast milk has been demonstrated. The patient received a dose of 40 mg/day, and it was estimated that her nursing infant would receive 1.5% of the maternal dose (Rollman & Pihl-Lundin, 1990). In animal studies, acitretin in breast milk has been associated with a decrease in pup survival (Kistler & Hummler, 1985).
C) ANIMAL STUDIES 1) ACITRETIN a) In animal studies, acitretin in breast milk has been associated with a decrease in pup survival (Kistler & Hummler, 1985).
3.20.5) FERTILITY
A) LACK OF INFORMATION 1) FLUOCINOLONE ACETONIDE/HYDROQUINONE/TRETINOIN a) At the time of this review, no data were available to assess the potential effects in fertility from exposure to this combination product (Prod Info TRI-LUMA(R) topical cream, 2013).
B) MALE FERTILITY 1) There were no reports of decreases in sperm count or concentration or changes in sperm motility or morphology in men administered acitretin 30 to 50 mg/day for 12 weeks. No deleterious effects were observed on testosterone production, luteinizing hormone, follicle-stimulating hormone, or hypothalamic-pituitary axis (Prod Info SORIATANE(R) oral capsules, 2015).
C) ANIMAL STUDIES 1) ACITRETIN a) There were no reports of impaired fertility in animals administered acitretin at doses approximately one-half of the recommended human dose. Testicular changes (eg, reversible mild to moderate spermatogenic arrest, appearance of multinucleated giant cells) were reported in animals administered acitretin at doses up to 50 mg/kg/day (Prod Info SORIATANE(R) oral capsules, 2015).
2) TRETINOIN a) RATS: No fertility effects were observed in rats given oral tretinoin 2 mg/kg/day (64 times the recommended clinical dose based on body surface area) (Prod Info VELTIN(TM) topical gel, 2010).
3) FLUOCINOLONE ACETONIDE/HYDROQUINONE/TRETINOIN a) RATS, MINI-PIGS: Topical therapy with a 10-fold dilution of fluocinolone acetonide/hydroquinone/tretinoin cream in pregnant rats revealed no effects on the traditional parameters used to assess fertility. However, topical treatment of male mini pigs with the full-strength of fluocinolone acetonide/hydroquinone/tretinoin for 6 months caused small testes and severe hypospermia (Prod Info TRI-LUMA(R) topical cream, 2013).
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Carcinogenicity |
3.21.2) SUMMARY/HUMAN
A) At the time of this review, the manufacturer does not report any carcinogenic potential of tretinoin in humans. In animal studies, topical doses of tretinoin did not produce drug related tumors; however, it may enhance the tumorigenic potential of carcinogenic doses of UVA and UVB light.
3.21.4) ANIMAL STUDIES
A) FLUOCINOLONE/HYDROQUINONE/TRETINOIN 1) Topical application of fluocinolone/hydroquinone/tretinoin in fixed combinations equivalent to 10%, 25%, 50%, and 100% in male and female SD rats for a duration of 24 months at dosages that approximated 10, 4000 and 50 mcg/kg/day (corresponding to dosages of 60, 24,000 and 300 mcg/m(2) day, respectively) resulted in statistically significant increases in the incidences of islet cell adenomas, combined islet cell adenomas and carcinomas of the pancreas in both males and females (Prod Info TRI-LUMA(R) topical cream, 2013).
B) TRETINOIN 1) Tretinoin exposure in hairless albino mice may enhance the tumorigenic potential of carcinogenic doses of both UVA and UVB light from a solar simulator (Prod Info TRI-LUMA(R) topical cream, 2013; Prod Info AVITA(R) topical gel, 2011). In a study of dark pigmented mice, increased pigmentation did not alter the enhancement of photocarcinogenesis by 0.05% tretinoin (Prod Info TRI-LUMA(R) topical cream, 2013). In an older study, lightly pigmented hairless mice, the incidence and rate of development of skin tumors were reduced or no effect was observed with tretinoin treatment following exposure to UVA and UVB light at carcinogenic doses (Prod Info AVITA(R) topical gel, 2011).
C) LACK OF EFFECT 1) FLUOCINOLONE/HYDROQUINONE/TRETINOIN a) Topical application of fluocinolone/hydroquinone/tretinoin in fixed combinations equivalent to 10%, 50%, 100% and 150% of the clinical concentrations on male and female CD-1 mice did not result in significant changes in tumor incidence after 24 months (Prod Info TRI-LUMA(R) topical cream, 2013).
2) TRETINOIN a) During a dermal mouse carcinogenicity study, administration of tretinoin 0.027 mg/kg, 0.072 mg/kg, and 0.225 mg/kg (approximately 0.003%, 0.008%, and 0.025% gel, respectively) in CD-1 mice for up to 2 years resulted in no drug related tumors (Prod Info AVITA(R) topical gel, 2011).
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Genotoxicity |
A) At the time of this review, no adequate and well-controlled genotoxicity or mutagenicity studies have been conducted in humans. In animal studies, tretinoin was not mutagenic.
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