Clinical medicine profile
Tretinoin, topical
Retinoid [EPC]
- Route
- See product SmPC
- Schedule
- POM
- ATC
- Not assigned
- PPB status
- registered
Safety essentials
The information most likely to change a prescribing or dispensing decision.
WARNING: EMBRYO-FETAL TOXICITY and DIFFERENTIATION SYNDROME • Tretinoin capsules can cause embryo-fetal loss and malformations when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Females of reproductive potential must have a negative pregnancy test before initiating tretinoin capsules. Advise females of reproductive potential to use two effective methods of contraception during treatment with tretinoin capsules and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with tretinoin capsules and for 1 week after the last dose [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)] . • Differentiation Syndrome, which can be life-threatening or fatal, occurred in about 26% of patients with APL who received tretinoin capsules. At first signs or symptoms of this syndrome, immediately initiate high-dose corticosteroid therapy and hemodynamic monitoring until resolution of signs and symptoms. Consider withholding tretinoin capsules for moderate and severe Differentiation Syndrome until resolution [see Warnings and Precautions (5.2)] . WARNING: EMBRYO-FETAL TOXICITY and DIFFERENTIATION SYNDROME See full prescribing information for complete boxed warning. • Embryo-Fetal Toxicity: tretinoin capsules can cause embryo-fetal loss and malformations when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Females of reproductive potential must have a negative pregnancy test before initiating tretinoin capsules. Advise females of reproductive potential to use two effective methods of contraception during treatment with tretinoin capsules and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with tretinoin capsules and for 1 week after the last dose. (5.1, 8.1, 8.3) • Differentiation Syndrome, which can be life-threatening or fatal, occurred in about 26% of patients with APL who received tretinoin capsules. At first signs or symptoms of this syndrome, immediately initiate high-dose corticosteroid therapy and hemodynamic monitoring until resolution of signs and symptoms. Consider withholding tretinoin capsules for moderate and severe Differentiation Syndrome until resolution. (5.2)
Contraindications
- 4 CONTRAINDICATIONS Tretinoin capsules are contraindicated in patients with a known hypersensitivity to tretinoin capsules, any of its components, or other retinoids.
- Reactions have included rash, pruritus, face edema, and dyspnea [see Adverse Reactions ( 6.1 )].
- Hypersensitivity to tretinoin capsules, any of its components, or other retinoids
Precautions
- WARNINGS Orally and parenterally administered clindamycin has been associated with severe colitis which may result in patient death.
- Use of the topical formulation of clindamycin results in absorption of the antibiotic from the skin surface.
- Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical and systemic clindamycin.
- Studies indicate a toxin(s) produced by clostridia is one primary cause of antibiotic-associated colitis.
- The colitis is usually characterized by severe persistent diarrhea and severe abdominal cramps and may be associated with the passage of blood and mucus.
- Endoscopic examination may reveal pseudomembranous colitis.
- Stool culture for Clostridium difficile and stool assay for C. difficile toxin may be helpful diagnostically.
- When significant diarrhea occurs, the drug should be discontinued.
- Large bowel endoscopy should be considered to establish a definitive diagnosis in cases of severe diarrhea.
- Antiperistaltic agents such as opiates and diphenoxylate with atropine may prolong and/or worsen the condition.
- Vancomycin has been found to be effective in the treatment of antibiotic-associated pseudomembranous colitis produced by Clostridium difficile .
- The usual adult dosage is 500 milligrams to 2 grams of vancomycin orally per day in three to four divided doses administered for 7 to 10 days.
Dosing matrix
Population and organ-function guidance, shown together for faster comparison.
2 DOSAGE AND ADMINISTRATION • The recommended dosage of tretinoin capsules is 22.5 mg/m 2 orally twice daily until complete remission. ( 2.2 ) • Discontinue 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first. ( 2.2 ) 2.1 Important Safety Information Verify pregnancy status in females of reproductive potential prior to initiating tretinoin capsules. Females of reproductive potential must have a negative pregnancy test before initiating tretinoin capsules [see Use in Specific Populations (8.3)] . 2.2 Recommended Dosage The recommended dosage of tretinoin capsules is 22.5 mg/m 2 orally twice daily until complete remission is documented. Discontinue tretinoin capsules 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first. Discontinue tretinoin capsules if the t(15;17) translocation or PML/RARα fusion has not been identified [see Warnings and Precautions (5.3)] . Take tretinoin capsules with a meal. Swallow tretinoin capsules whole with water. Do not chew, dissolve, or open capsule. Do not take a missed dose of tretinoin capsules unless it is more than 10 hours until the next scheduled dose. If vomiting occurs after tretinoin capsules administration, do not take an additional dose, but continue with the next scheduled dose. 2.1 Important Safety Information Verify pregnancy status in females of reproductive potential prior to initiating tretinoin capsules. Females of reproductive potential must have a negative pregnancy test before initiating tretinoin capsules [see Use in Specific Populations (8.3)] . 2.2 Recommended Dosage The recommended dosage of tretinoin capsules is 22.5 mg/m 2 orally twice daily until complete remission is documented. Discontinue tretinoin capsules 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first. Discontinue tretinoin capsules if the t(15;17) translocation or PML/RARα fusion has not been identified [see Warnings and Precautions (5.3)] . Take tretinoin capsules with a meal. Swallow tretinoin capsules whole with water. Do not chew, dissolve, or open capsule. Do not take a missed dose of tretinoin capsules unless it is more than 10 hours until the next scheduled dose. If vomiting occurs after tretinoin capsules administration, do not take an additional dose, but continue with the next scheduled dose.
8.4 Pediatric Use Safety and effectiveness of tretinoin capsules have been established in pediatric patients 1 year of age and older and the information on this use is discussed throughout the labeling. The maximum tolerated dose is lower in pediatric patients compared to adults. Some pediatric patients experience severe headache and intracranial hypertension, which required management with an analgesic and a lumbar puncture. Dose reduction may be considered for pediatric patients experiencing serious and/or intolerable adverse reactions. Safety and effectiveness in pediatric patients less than 1 year of age have not been established.
Review renal impairment dosing; many agents need CrCl/eGFR adjustment.
- CrCl 0–120: Confirm renal dosing in product SmPC / primary label.
Review hepatic impairment dosing; monitor LFTs if agent is hepatically cleared or hepatotoxic.
Use, effects & interactions
Indications
- 1 INDICATIONS AND USAGE Tretinoin capsules are indicated for the induction of remission in adults and pediatric patients 1 year of age and older with acute promyelocytic leukemia (APL) characterized by the presence of the t(15;17) translocation or PML/RARα gene expression, and who are refractory to or who have relapsed from anthracycline chemotherapy or for whom anthracycline-based chemotherapy is contraindicated.
- Tretinoin capsules are a retinoid indicated for induction of remission in adults and pediatric patients 1 year of age and older with acute promyelocytic leukemia (APL), characterized by presence of t(15;17) translocation or presence of PML/RARα gene expression, and who are refractory to or who have relapsed from anthracycline chemotherapy or for whom anthracycline-based chemotherapy is contraindicated.
Adverse effects
- ADVERSE REACTIONS In 18 clinical studies of various formulations of clindamycin phosphate using placebo vehicle and/or active comparator drugs as controls, patients experienced a number of treatment emergent adverse dermatologic events [see table below].
- Number of Patients Reporting Events Treatment Emergent Adverse Event Solution n=553(%) Gel n=148(%) Lotion n=160(%) Burning 62 (11) 15 (10) 17 (11) Itching 36 ( 7) 15 (10) 17 (11) Burning/Itching 60 (11) # ( – ) # ( – ) Dryness 105 (19) 34 (23) 29 (18) Erythema 86 (16) 10 ( 7) 22 (14) Oiliness/Oily Skin 8 ( 1) 26 (18) 12* (10) Peeling 61 (11) # ( – ) 11 ( 7) # not recorded * of 126 subjects Orally and parenterally administered clindamycin has been associated with severe colitis which may end fatally.
- Cases of diarrhea, bloody diarrhea and colitis (including pseudomembranous colitis) have been reported as adverse reactions in patients treated with oral and parenteral formulations of clindamycin and rarely with topical clindamycin (see WARNINGS ).
- Abdominal pain, gastrointestinal disturbances, gram-negative folliculitis, eye pain and contact dermatitis have also been reported in association with the use of topical formulations of clindamycin.
- To report SUSPECTED ADVERSE REACTIONS, contact Perrigo at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
Drug interactions
Open multi-drug checker ↗- Professional use: confirm indication, dose, duration, monitoring and patient counselling points against current Kenya STG / EML and the product SmPC.
- Document allergy status and key interactions.
Mechanism & disposition
12.
Read complete mechanism
12.1 Mechanism of Action Tretinoin induces cytodifferentiation and decreased proliferation of APL cells in culture and in vivo . In APL patients, tretinoin treatment produces an initial maturation of the primitive promyelocytes derived from the leukemic clone, followed by a repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells in patients achieving complete remission (CR). The exact mechanism of action of tretinoin in APL is unknown.
Product-specific
Product-specific
See product SmPC
Time to reach peak concentration was between 1 and 2 hours. The absolute bioavailability of tretinoin capsules was approximately 50%. Effect of Food The effect of food on the absorption of tretinoin capsules has not been characterized. Food increases the absorption of retinoids,...
The apparent volume of distribution of tretinoin has not been determined. Protein binding is greater than 95%, predominately to albumin. Plasma protein binding remains constant over the concentration range of 10 to 500 ng/mL.
Tretinoin induced its own metabolism with plasma concentrations after 1 week of continuous therapy decreased to one-third of their day 1 values. Tretinoin is metabolized by cytochrome P450 enzymes, CYP3A4, 2C8, and 2E and undergoes glucuronidation by UGT2B7. Metabolites include 9...
The terminal elimination
of tretinoin following initial dosing is 0.5 to 2 hours in patients with APL.
Pregnancy, lactation & diet
8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action [see Clinical Pharmacology ( 12.1 )], tretinoin capsules can cause embryo-fetal loss and malformations when administered to a pregnant woman. Tretinoin capsules are a retinoid and there is an increased risk of major congenital malformations, spontaneous abortions and premature births following exposure to retinoids during pregnancy in humans. Tretinoin was teratogenic and embryotoxic in mice, rats, hamsters, rabbits and pigtail monkeys at doses less than the human dose on a mg/m 2 basis (see Data) . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data Tretinoin capsules are a retinoid and increased spontaneous abortions and major fetal abnormalities related to the use of retinoids have been documented in humans. Reported malformations include abnormalities of the central nervous system, musculoskeletal system, external ear, eye, thymus and great vessels; and facial dysmorphia, cleft palate, and parathyroid hormone deficiency. Some of these abnormalities were fatal. IQ scores less than 85, with or without obvious CNS abnormalities, have been reported in pediatrics exposed to retinoids in utero . Animal Data Tretinoin causes fetal resorptions and a decrease in live fetuses in all animals studied. Gross external, soft tissue and skeletal alterations occurred at doses higher 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, the only dose tested, in pigtail monkeys (about 1/20, 1/4, and 1/2 and 4 times the human dose, respectively, on a mg/m 2 basis).
Nursing Mothers It is not known whether clindamycin is excreted in breast milk following use of clindamycin phosphate. However, orally and parenterally administered clindamycin has been reported to appear in breast milk. Clindamycin has the potential to cause adverse effects on the breast-fed infant's gastrointestinal flora. Monitor the breast-fed infant for possible adverse effects on the gastrointestinal flora, such as diarrhea, candidiasis (thrush, diaper rash) or rarely, blood in the stool indicating possible antibiotic-associated colitis. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for clindamycin and any potential adverse effects on the breast-fed child from clindamycin or from the underlying maternal condition. Clinical Considerations If used during lactation and clindamycin phosphate topical lotion is applied to the chest, care should be taken to avoid accidental ingestion by the infant.
Brands & loaded prices
| Brand | Manufacturer | Pack | Observed price |
|---|---|---|---|
| Acnesol | Universal | tabs 25gm | Unavailable |
Sources & review state
Decision support only. Confirm patient-specific decisions against the current product SmPC, Kenya STG/EML, and professional judgement.