Tretinoin Capsule
FDA Label NDC 68084-075

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 [seeWarnings 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 [seeWarnings and Precautions (5.2)].

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.

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 [seeUse in Specific Populations (8.3)].

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 [seeWarnings 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.

Capsules: 10 mg, two-tone (lengthwise) with reddish-brown opaque and yellow gelatin shell, imprinted with “TR” with black ink on the yellow side.

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. [seeAdverse Reactions (6.1)].

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 has teratogenic and embryotoxic effects in mice, rats, hamsters, rabbits and pigtail monkeys at doses less than the human dose on a mg/m ² basis.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use 2 effective methods of contraception during treatment with tretinoin capsules and for 1 month following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with tretinoin capsules and for 1 week following the last dose [seeUse in Specific Populations (8.1, 8.3)] .

Differentiation Syndrome, which may be life-threatening or fatal, occurred in about 26% of patients with APL who received tretinoin capsules [seeAdverse Reactions (6.1)]. Symptoms include fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, renal, and multi-organ failure. This syndrome has been accompanied by impaired myocardial contractility and episodic hypotension and it has been observed with or without concomitant leukocytosis. This syndrome generally occurs during the first month of treatment, as early as following the first dose. Endotracheal intubation and mechanical ventilation were required in some cases due to progressive hypoxemia and several patients have died with multi-organ failure.

At the first signs or symptoms of this syndrome, immediately administer dexamethasone 10 mg intravenously every 12 hours until signs and symptoms have abated for at least 3 days and initiate hemodynamic monitoring until resolution of signs and symptoms. Consider withholding tretinoin capsules for moderate and severe differentiation syndrome until resolution [seeAdverse Reactions (6.1)].

Tretinoin capsules may be initiated based on the morphological diagnosis of acute promyelocytic leukemia (APL). Confirm the diagnosis of APL by detection of the t(15;17) translocation using cytogenetic studies or PML/RARα fusion using molecular diagnostic techniques. Tretinoin capsules not recommended for use in patients without these genetic markers [seeIndications and Usage (1)].

Rapidly evolving leukocytosis, which can be life-threatening, occurred in about 40% of patients with APL who received tretinoin capsules [seeAdverse Reactions (6.1)]. Patients who present with a baseline white blood cell count (WBC) > 5 × 10 ⁹/L have an increased risk. Patients who receive chemotherapy with tretinoin capsules may be at a reduced risk. Rapidly evolving leukocytosis is associated with a higher risk of life-threatening complications.

Consider administering cytoreductive chemotherapy (including an anthracycline if not contraindicated or hydroxyurea) with tretinoin capsules in the setting of leukocytosis, as clinically indicated.

Retinoids, including tretinoin capsules, have been associated with intracranial hypertension, especially in pediatric patients. Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances. Evaluate patients with these symptoms for intracranial hypertension, and, if present, institute appropriate care in concert with neurological assessment. Consider interruption, dose reduction, or discontinuation of tretinoin capsules as appropriate.

The concomitant use of other products (e.g., tetracyclines) that can cause intracranial hypertension may increase the risk. Avoid concomitant use of tretinoin capsules with other products that can cause intracranial hypertension [seeDrug Interactions (7.2)].

Hypercholesterolemia and/or hypertriglyceridemia has occurred in up to 60% of patients who received tretinoin capsules. These changes may be reversible upon completion of treatment. The clinical consequences of increased triglycerides and cholesterol are unknown, but venous thrombosis and myocardial infarction have been reported in patients who ordinarily are at low risk for such complications.

Monitor fasting triglycerides and cholesterol at baseline and periodically during treatment.

Elevated liver function test results occurred in 50% to 60% of patients during treatment with tretinoin capsules. Most of these abnormalities resolved without interruption of tretinoin capsules or after completion of treatment.

Monitor liver function test at baseline and during treatment as clinically indicated. Consider withholding tretinoin capsules if liver function test results increase to greater than 5 times the upper limit of normal values until resolution.

Venous and arterial thromboembolic events, including cerebrovascular accident, myocardial infarction and renal infarct have been reported with tretinoin capsules [seeAdverse Reactions (6.2)]. These events may occur during the first month of treatment. Patients taking anti-fibrinolytic agents may have an increased risk.

Avoid concomitant use of tretinoin capsules and anti-fibrinolytic agents, such as tranexamic acid, aminocaproic acid or aprotinin [seeDrug Interactions (7.4)].

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Differentiation Syndrome [seeWarnings and Precautions (5.2)]
• Leukocytosis [seeWarnings and Precautions (5.4)]
• Intracranial hypertension [seeWarnings and Precautions (5.5)]
• Lipid abnormalities [seeWarnings and Precautions (5.6)]
• Hepatotoxicity [seeWarnings and Precautions (5.7)]
• Thromboembolic events [seeWarnings and Precautions (5.8)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Acute Promyelocytic Leukemia
The safety of tretinoin capsules was evaluated in patients with APL who received tretinoin capsules at a dose of 22.5 mg/m ² orally twice daily [seeClinical Studies (14)].

The most common adverse reactions (≥30%) were headache, fever, skin/mucous membrane dryness, bone pain, malaise, shivering, upper respiratory tract disorders, dyspnea, hemorrhage, infections, nausea/vomiting, rash, peripheral edema, leukocytosis, pain, gastrointestinal hemorrhage, chest discomfort, abdominal pain.

Table 1 summarizes the adverse reactions for patients with APL.

Adverse reactions that occurred in <10% of patients who received tretinoin capsules include:

• Hepatobiliary disorders: Hepatosplenomegaly (9%), hepatitis (3%), unspecified liver disorder (3%).
• Musculoskeletal and connective tissue disorders: Flank pain (9%), bone inflammation (3%).
• Nervous system disorders: Agitation (9%), cerebral hemorrhage (9%), intracranial hypertension (9%), hallucination (6%), abnormal gait, agnosia, aphasia, asterixis, cerebellar edema, cerebellar disorders, convulsions, coma, CNS depression, dysarthria, encephalopathy, facial paralysis, hemiplegia, hyporeflexia, hypotaxia, no light reflex, neurologic reaction, spinal cord disorder, stroke, tremor, leg weakness, unconsciousness, dementia, forgetfulness, somnolence, and slow speech (3% each).
• Renal and urinary disorders: Dysuria (9%), acute renal failure, micturition frequency, renal tubular necrosis, and enlarged prostate (3% each).
• Respiratory, thoracic and mediastinal disorders: Lower respiratory tract disorders (9%), pulmonary infiltration (6%), bronchial asthma, pulmonary edema, larynx edema, and unspecified pulmonary disease (3% each).
• Infections and infestations: Cellulitis (8%).
• Blood and lymphatic system disorders: Lymph disorders (6%).
• Cardiovascular disorders: Cardiac failure (6%), cardiac arrest, myocardial infarction, enlarged heart, heart murmur, myocarditis, pericarditis, and secondary cardiomyopathy (3% each).
• Ear and labyrinth disorders: Hearing loss and other unspecified auricular disorders (6%), irreversible hearing loss (<1%).
• General disorders: Face edema (6%), pallor (6%), hypothermia (3%).
• Metabolism and nutrition disorders: Fluid imbalance (6%), acidosis (3%).
• Eye disorders: Changed visual acuity (6%), visual field defects (3%).
• Gastrointestinal disorders: Ascites, ulcer (3% each).
• Vascular disorders: Ischemia and pulmonary hypertension (3% each).

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Erythema nodosum, basophilia and hyperhistaminemia, Sweet’s Syndrome, organomegaly, hypercalcemia, pancreatitis, myositis, thrombosis (both venous and arterial), thrombocytosis, genital ulceration and vasculitis, predominantly involving the skin.

Strong CYP3A Inhibitors
The coadministration of tretinoin capsules with ketoconazole, a strong CYP3A4 inhibitor, increased tretinoin plasma concentration, which may increase the risk of adverse reactions [seeClinical Pharmacology (12.3)]. Avoid coadministration of tretinoin capsules with strong CYP3A inhibitors if possible. Monitor patients taking a strong CYP3A inhibitor with tretinoin capsules more frequently for adverse reactions.

Strong CYP3A Inducers
The coadministration of tretinoin capsules with strong CYP3A4 inducers may decrease tretinoin plasma concentrations, which may reduce its efficacy. Avoid coadministration with strong CYP3A inducers if possible.

Intracranial hypertension has been reported in patients who received tretinoin capsules and concomitant use of other products that can cause intracranial hypertension, such as tetracyclines, may increase the risk. Avoid concomitant use of tretinoin capsules with other products agents that can cause intracranial hypertension [seeWarnings and Precautions (5.5)].

The concomitant use of vitamin A with tretinoin capsules may lead to vitamin A related adverse reactions. Avoid concomitant use of tretinoin capsules with vitamin A.

Fatal thrombotic complications have been reported in patients who have received tretinoin capsules and concomitant use of anti-fibrinolytic agents may increase the risk. Avoid concomitant use of tretinoin capsules with anti-fibrinolytic agents [seeWarnings and Precautions (5.8)].

Risk Summary
Based on findings in animals and its mechanism of action [seeClinical 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
Trentoin 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).

There are no data on the presence of tretinoin in human milk, the effects on the breastfeed child or the effects on milk production. Because of the potential for serious adverse reactions from tretinoin capsules in breastfed infants, advise women not to breastfed during treatment with tretinoin capsules and for 1 week after the last dose.

Tretinoin capsules can cause embryo-fetal loss and malformations when administered to a pregnant woman [seeUse in Specific Populations (8.1)].

Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating tretinoin capsules. Females of reproductive potential must have a negative pregnancy test within 1 week prior to initiating tretinoin capsules with a sensitivity of at least 50 mIU/mL.

Contraception
Females
Advise females of reproductive potential to abstain continuously from sexual intercourse or to use two effective methods of contraception. Counsel patients to use two effective methods of contraception during treatment with tretinoin capsules and for 1 month after the last dose. Two methods of effective contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Refer females of reproductive potential to a qualified provider of contraceptive methods, if needed.

Males
Advise males with female partners of reproductive potential to use effective contraception during and after treatment with tretinoin capsules and for 1 week after the last dose.

Infertility
Males
Based on testicular toxicities observed in dogs, tretinoin capsules may impair male fertility [seeNonclinical Toxicology (13.1)]. The reversibility of effect on fertility is unknown.

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.

Across clinical studies of tretinoin capsules, 21% were 60 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

In case of overdose with tretinoin capsules, reversible signs of hypervitaminosis A (headache, nausea, vomiting, mucocutaneous symptoms) can appear. Overdosage with other retinoids has been associated with transient headache, facial flushing, cheilosis, abdominal pain, dizziness and ataxia. These symptoms have quickly resolved without apparent residual effects.

There is no specific treatment in the case of an overdose; however, it is important that the patient be treated in a special hematological unit.

Tretinoin is a retinoid. The chemical name is all-trans retinoic acid. The molecular formula is C ₂₀H ₂₈O ₂ and the molecular weight is 300.44 g/mol. The structural formula is:

The Molecular Formula For Tretinoin. (Tretinoin 1)

It is a yellow to light orange, crystalline powder with melting point at about 182°C (with decomposition). Tretinoin is practically insoluble in water, sparingly soluble in methylene chloride, and slightly soluble in ethanol (96%).

Tretinoin capsules are available as capsules containing 10 mg tretinoin for oral use. Each capsule also contains butylated hydroxyanisole, edetate disodium, soybean oil, hydrogenated vegetable oils, medium chain triglycerides, soya lecithin, and yellow beeswax. The gelatin capsule shell contains gelatin, glycerin, yellow iron oxide, red iron oxide and titanium dioxide. Capsules are printed with edible black ink, which consist of propylene glycol, iron oxide black, polyvinyl acetate phthalate and polyethylene glycol 400.

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.

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of tretinoin capsules have not been characterized.

Following the administration of tretinoin capsules 22.5 mg/m ² orally twice daily, the mean ± SD peak tretinoin concentrations after the first dose was 394 ± 89 and after 1 week of continuous treatment was 138 ± 139 ng/mL, while area under the curve (AUC) after the first dose was 537 ± 191 ng·h/mL and after 1 week of continuous treatment was 249 ± 185 ng·h/mL.

Absorption
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, as a class.

Distribution
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.

Elimination
The terminal elimination half-life of tretinoin following initial dosing is 0.5 to 2 hours in patients with APL.

Metabolism
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- cisretinoic acid, 13- cisretinoic acid, 4-oxo transretinoic acid, 4-oxo cisretinoic acid, and 4-oxo transretinoic acid glucuronide. The metabolites 4-oxo retinoic acid and 4-oxo transretinoic acid glucuronide have one-third of the pharmacological activity of the parent compound.

Excretion
Following administration of radiolabeled tretinoin 2.75 mg and 50 mg (0.53 to 9.6 times the approved recommended dosage based on 1.7 m ²), approximately 63% of radioactivity was recovered in the urine within 72 hours and 31% appeared in the feces within 6 days.

Specific Populations
The effect of age, sex, race, renal impairment, and hepatic impairment on the pharmacokinetics of tretinoin is unknown.

Drug Interaction Studies
Clinical Studies
Coadministration of ketoconazole (strong CYP3A inhibitor) increased tretinoin AUC by 72%.

In Vitro Studies
Effect of Tretinoin on Transporters:Tretinoin does not inhibit P-gp and BCRP in vitro.

No 2-year carcinogenicity studies in rodents have been conducted with tretinoin. In a carcinogenicity study, female B5D2F1 mice pretreated with a carcinogen diethylnitrosamine (DEN, intraperitoneal 50 mg/kg and 100 mg/kg) received dietary supplement of all-trans-retinoic acid (tretinoin) for 12 months. Tretinoin at a dose of 30 mg/kg/day in the diet (about 2 times the human dose on a mg/m ² basis) was shown to increase the rate of DEN-induced mouse hepatocellular carcinomas. Tretinoin in combination with 50 mg/kg of DEN also increased the incidence of hemangiomas and hemangiosarcomas.

Tretinoin was negative when tested in the Ames and Chinese hamster V79 cell HGPRT assays for mutagenicity. A 2-fold increase in the sister chromatid exchange (SCE) has been demonstrated in human diploid fibroblasts, but other chromosome aberration assays, including an in vitro assay in human peripheral lymphocytes and an in vivo mouse micronucleus assay, did not show a clastogenic or aneuploidogenic effect.

Adverse effects on fertility and reproductive performance were not observed in studies conducted in rats at doses up to 5 mg/kg/day (about 2/3 the human dose on a mg/m ² basis). In a 6-week toxicology study in dogs, testicular degeneration, with increased numbers of immature spermatozoa, were observed at 10 mg/kg/day (about 4 times the equivalent human dose in mg/m ²).

The efficacy of tretinoin capsules have been evaluated in 114 previously treated patients and in 67 previously untreated (“de novo”) patients with APL in one open-label, uncontrolled single investigator clinical study (Memorial Sloan-Kettering Cancer Center [MSKCC]) and in two cohorts of compassionate cases treated by multiple investigators under the auspices of the National Cancer Institute (NCI). Patients received tretinoin capsules 22.5 mg/m ² orally twice daily for up to 90 days following the first dose or 30 days following achievement of complete remission. Efficacy results are shown Table 2.

NR = Not Reached

NA = Not Available

The median time to complete remission was between 40 and 50 days (range: 2 to 120 days). Most patients received cytotoxic chemotherapy during the remission phase.

Ten of 15 pediatric cases achieved complete remission (8 of 10 males and 2 of 5 females).

Tretinoin capsules are supplied as 10 mg capsules, two-tone (lengthwise) with reddish-brown opaque and yellow gelatin shell, imprinted with “TR” with black ink on the yellow side. Supplied in:
Unit dose packages of 30 (3 x 10) NDC 68084-075-21

Store at 20°C to 25°C (68°F to 77°F); [see USP Controlled Room Temperature].

Protect from light.

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

Embryo-Fetal Toxicity
Advise female patients of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [seeWarnings and Precautions (5.1)andUse in Specific Populations (8.1, 8.3)] .

Advise females of reproductive potential to use 2 methods of effective contraception during treatment with tretinoin capsules and for 1 month after the last dose [seeUse in Specific Populations (8.3)].

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 [seeUse in Specific Populations (8.3)].

Differentiation Syndrome
Advise patients that tretinoin capsules can cause differentiation syndrome. Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, decreased urinary output, low blood pressure, rapid weight gain, or swelling of their arms or legs, to their healthcare provider for further evaluation [seeWarnings and Precautions (5.2)].

Patients Without t(15;17) Translocation or PML/RARα Fusion
Advise patients that tretinoin capsules are not recommended for use in patients without t(15;17) translocation or PML/RARα fusion [seeWarnings and Precautions (5.3)].

Leukocytosis
Inform patients that rapidly evolving leukocytosis, which can be life-threatening, can occur during treatment with tretinoin capsules [seeWarnings and Precautions (5.4)].

Intracranial Hypertension
Advise patients that tretinoin capsules can cause intracranial hypertension, especially in pediatric patients. Ask patients to immediately report any symptoms suggestive of intracranial hypertension, such as headache, nausea, vomiting, and visual disturbances [seeWarnings and Precautions (5.5)].

Lipid Abnormalities
Inform patients that hypercholesterolemia and/or hypertriglyceridemia can occur during treatment with tretinoin capsules. Advise patients on the need for monitoring fasting triglycerides and cholesterol [seeWarnings and Precautions (5.6)].

Hepatotoxicity
Advise patients that tretinoin capsules can cause elevated liver function tests. Advise patients on the need for monitoring of liver function tests [seeWarnings and Precautions (5.7)].

Thromboembolic Events
Inform patients that venous and arterial thromboembolic events, including cerebrovascular accident, myocardial infarction and renal infarct can occur during treatment with tretinoin capsules [seeWarnings and Precautions (5.8)].

Lactation
Advise women not to breastfeed during treatment with tretinoin capsules and for 1 week after the last dose [seeUse in Specific Populations (8.2)].

Administration Instructions
Advise patients to swallow tretinoin capsules whole with water. Advise patients not to chew, dissolve, or open capsules. Advise patients not to take a missed dose of tretinoin capsules unless it is more than 10 hours until the next scheduled dose. Advise patients that if vomiting occurs after tretinoin capsules administration, that they should not take an additional dose, but continue with the next scheduled dose [seeDosage and Administration (2.2)].

Effects on Ability to Drive and Use Machines
Advise patients that the ability to drive or operate machinery might be impaired when treated with tretinoin capsules, particularly if patients are experiencing dizziness or severe headache.

American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Par Pharmaceutical as follows:
(10 mg / 30 UD) NDC 68084-075-21 packaged from NDC 10370-268

Distributed by:
American Health Packaging
Columbus, OH 43217

8207521/0125

10 mg Tretinoin Capsules Carton.jpg (Image 01)

NDC 68084- 075-21

Tretinoin
Capsules

10 mg

30 Capsules (3 x 10) Rx Only

PHARMACIST: Dispense with Patient Information to each patient.

PATIENT: READ INFORMATION LEAFLET CAREFULLY

Each Capsule Contains:
Tretinoin........................................................10 mg

Usual Dosage: See full prescribing information.

Store at 20° to 25°C (68° to 77°F); excursions
permitted between 15° to 30°C (59° to 86°F)
[see USP Controlled Room Temperature].
Protect from light.

FOR YOUR PROTECTION: Do not use if blister
is torn or broken.

The drug product contained in this package is from
NDC # 10370-268, Par Pharmaceutical.

Distributed by: American Health Packaging, Columbus, Ohio 43217

007521
0207521/0924

Tretinoin
Capsule

10 mg