TRETINOIN: 4,138 Adverse Event Reports & Safety Profile

Tretinoin Gel Microsphere, 0.1%, 0.08% and 0.04% is a white to very pale yellow opaque gel for topical treatment of acne vulgaris. Chemically, tretinoin is all-trans-retinoic acid, also known as (all-E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid. It is a member of the retinoid class of compounds and a metabolite of naturally occurring Vitamin A. Tretinoin has a molecular weight of 300.44, a molecular formula of C 20 H 28 O 2 and the following chemical structure: Each gram of Tretinoin Gel Microsphere, 0.1%, contains 1 mg of tretinoin. Each gram of Tretinoin Gel Microsphere, 0.08%, contains 0.8 mg of tretinoin. Each gram of Tretinoin Gel Microsphere, 0.04%, contains 0.4 mg of tretinoin. The formulation contains methyl methacrylate/glycol dimethacrylate crosspolymer (MICROSPONGE ® System), propylene glycol dicaprylate/dicaprate and butylated hydroxytoluene to enable inclusion of the active ingredient, tretinoin, in an aqueous gel. Other components consist of benzyl alcohol, butylated hydroxytoluene, carbomer 974P, cyclomethicone and dimethicone copolyol, disodium EDTA, glycerin, PPG-20 methyl glucose ether distearate, propylene glycol, purified water, sorbic acid, and trolamine. chemstructure.jpg

INDICATIONS AND USAGE (To understand fully the indication for this product, please read the entire INDICATIONS AND USAGE section of the labeling.) RENOVA (tretinoin cream) 0.02% is indicated as an adjunctive agent (see second bullet point below) for use in the mitigation (palliation) of fine facial wrinkles in patients who use comprehensive skin care and sunlight avoidance programs. RENOVA (tretinoin cream) 0.02% DOES NOT ELIMINATE WRINKLES, REPAIR SUN-DAMAGED SKIN, REVERSE PHOTOAGING, or RESTORE MORE YOUTHFUL or YOUNGER SKIN. In double-blind, vehicle-controlled clinical studies, many patients in the vehicle group achieved desired palliative effects on fine wrinkling of facial skin with the use of comprehensive skin care and sunlight avoidance programs including sunscreens, protective clothing, and non-prescription emollient creams. RENOVA (tretinoin cream) 0.02% has NOT DEMONSTRATED A MITIGATING EFFECT on significant signs of chronic sunlight exposure such as coarse or deep wrinkling, tactile roughness, mottled hyperpigmentation, lentigines, telangiectasia, skin laxity, keratinocytic atypia, melanocytic atypia, or dermal elastosis. RENOVA (tretinoin cream) 0.02% should be used under medical supervision as an adjunct to a comprehensive skin care and sunlight avoidance program that includes the use of effective sunscreens (minimum SPF of 15) and protective clothing. Patients with visible actinic keratosis and patients with a history of skin cancer were excluded from clinical trials of RENOVA (tretinoin cream) 0.02%. Thus the effectiveness and safety of RENOVA (tretinoin cream) 0.02% in these populations are not known at this time. Neither the safety nor the effectiveness of RENOVA (tretinoin cream) 0.02% for the prevention or treatment of actinic keratoses or skin neoplasms has been established. Neither the safety nor the efficacy of using RENOVA (tretinoin cream) 0.02% daily for greater than 52 weeks has been established, and daily use beyond 52 weeks has not been systematically and histologically investigated in adequate and well-controlled trials (see WARNINGS ).

Clinical Trials

Four adequate and well-controlled multi-center trials and one single-center randomized, controlled trial were conducted involving a total of 324 evaluable patients treated with RENOVA (tretinoin cream) 0.02% and 332 evaluable patients treated with the vehicle cream on the face for 24 weeks with a comprehensive skin care and sun avoidance program, to assess the effects on fine and coarse wrinkling, mottled hyperpigmentation, tactile skin roughness, and laxity. Patients were evaluated at baseline on a 10-unit scale and changes from that baseline rating were categorized as follows: Worsening: Increase of 1 unit or more. No improvement: No change. Minimal improvement: Reduction of 1 unit. Mild improvement: Reduction of 2 units. Moderate improvement: Reduction of 3 units or more. In these trials, the fine and coarse wrinkling, mottled hyperpigmentation, tactile roughness, and laxity of the facial skin were thought to be caused by multiple factors which included intrinsic aging or environmental factors, such as chronic sunlight exposure. Two of the five trials provided adequate demonstration of efficacy for mitigation of fine facial wrinkling. No two of the five trials adequately demonstrated efficacy for mitigation of coarse wrinkling, mottled hyperpigmentation, tactile skin roughness, and laxity. Data for fine wrinkling (the indication for which RENOVA (tretinoin cream) 0.02% demonstrated efficacy) from all five trials (four studies in lightly pigmented subjects with Fitzpatrick Skin Types I-III and one study in darkly pigmented subjects with Fitzpatrick Skin Types IV-VI) is provided below: FINE WRINKLING IN LIGHTLY PIGMENTED SUBJECTS Subjects Using RENOVA (tretinoin cream) 0.02% + CSP * (N=279) Vehicle + CSP * (N=280) A single-center study (N=107) in darkly pigmented, mostly African-American, subjects with Fitzpatrick Skin Types IV-VI demonstrated minimal or mild improvement in fine facial wrinkling in 43% of patients using Vehicle + CSP compared to 29% of subjects using RENOVA (tretinoin cream) 0.02% + CSP * . Although fewer darkly pigmented subjects improved with RENOVA (tretinoin cream) 0.02% than with vehicle, these findings may reflect the small size of this study. * CSP – Comprehensive skin protection and sunlight avoidance programs including use of sunscreens, protective clothing, and non-prescription emollient creams.

Worsened

1% 3% No Change 40% 58% Minimal Improvement 35% 27% Mild Improvement 15% 9% Moderate Improvement 10% 3% Self-assessment of fine wrinkles after 24 weeks of treatment with either RENOVA (tretinoin cream) 0.02% or Vehicle from the four studies in lightly pigmented patients showed the following: No studies have been conducted comparing the facial irritation or efficacy of RENOVA (tretinoin cream) 0.02% to RENOVA (tretinoin cream) 0.05% (older marketed formulation). Patients may lose some of the mitigating effects of RENOVA (tretinoin cream) 0.02% after 12 weeks of discontinuation of RENOVA (tretinoin cream) 0.02% from their comprehensive skin care and sunlight avoidance program. figure1.jpg

AND ADMINISTRATION For topical use only. Not for ophthalmic, oral, or intravaginal use. Tretinoin gel (microsphere) should be applied once a day, in the evening, to the skin where acne lesions appear, using enough to cover the entire affected area in a thin layer. Areas to be treated should be cleansed thoroughly before the medication is applied. If medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. A transitory feeling of warmth or slight stinging may be noted on application. In cases where it has been necessary to temporarily discontinue therapy or to reduce the frequency of application, therapy may be resumed or the frequency of application increased as the patient becomes able to tolerate the treatment. Frequency of application should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance. Efficacy has not been established for less than once daily dosing frequencies. During the early weeks of therapy, an apparent exacerbation of inflammatory lesions may occur. If tolerated, this should not be considered a reason to discontinue therapy [see Adverse Reactions (6.1) ]. Therapeutic results may be noticed after two weeks, but more than seven weeks of therapy are required before consistent beneficial effects are observed. Tretinoin gel (microsphere) should be kept away from the eyes, the mouth, paranasal creases of the nose, and mucous membranes. Patients treated with tretinoin gel (microsphere) may use cosmetics. Concomitant topical medication, medicated or abrasive soaps and cleansers, products that have a strong drying effect, products with high concentrations of alcohol, astringents, or spices should be used with caution because of possible interaction with tretinoin. Avoid contact with the peel of limes. Particular caution should be exercised with the concomitant use of topical over-the-counter acne preparations containing benzoyl peroxide, sulfur, resorcinol, or salicylic acid with tretinoin gel (microsphere). It also is advisable to allow the effects of such preparations to subside before use of tretinoin gel (microsphere) is begun. Apply a thin layer of tretinoin gel (microsphere) once daily, before bedtime, to skin where lesions occur. Keep away from eyes, mouth, nasal creases, and mucous membranes. ( 2 ) Not for oral, ophthalmic, or intravaginal use. ( 2 )

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 (4)

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

• Differentiation Syndrome [see Warnings and Precautions ( 5.2 )]
• Leukocytosis [see Warnings and Precautions ( 5.4 )]
• Intracranial hypertension [see Warnings and Precautions ( 5.5 )]
• Lipid abnormalities [see Warnings and Precautions ( 5.6 )]
• Hepatotoxicity [see Warnings and Precautions ( 5.7 )]
• Thromboembolic events [see Warnings and Precautions ( 5.8 )] The most common adverse reactions (≥30%) are 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 ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience 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 [see Clinical 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.

Table

1.

Adverse

Reactions (≥ 10%) Occurring in Patients with APL Who Received Tretinoin Capsules Adverse Reaction Tretinoin Capsules All Grades (%) Nervous system disorders Headache 86 Dizziness 20 Paresthesias 17 Anxiety 17 Insomnia 14 Depression 14 Confusion 11 General disorders Fever 83 Skin/mucous membrane dryness 77 Malaise 66 Shivering 63 Peripheral edema 52 Pain 37 Chest discomfort 32 Edema 29 Mucositis 26 Weight increase 23 Anorexia 17 Weight decrease 17 Musculoskeletal and connective tissue disorders Bone pain 77 Myalgia 14 Respiratory, thoracic and mediastinal disorders Upper respiratory tract disorders 63 Dyspnea 60 Respiratory insufficiency 26 Pleural effusion 20 Rales 14 Expiratory wheezing 14 Pneumonia 14 Vascular disorders Hemorrhage 60 Gastrointestinal hemorrhage 34 Flushing 23 Hypotension 14 Hypertension 11 Phlebitis 11 Infections and infestations Infections 58 Gastrointestinal disorders Nausea/vomiting 57 Abdominal pain 31 Other gastrointestinal disorders 26 Diarrhea 23 Constipation 17 Dyspepsia 14 Abdominal distention 11 Skin and subcutaneous tissue disorders Rash 54 Pruritus 20 Increased sweating 20 Alopecia 14 Skin changes 14 Blood and lymphatic system disorders Leukocytosis 49 Differentiation syndrome 1 26 Disseminated intravascular coagulation 26 Ear and labyrinth disorders Earache or feeling of fullness in the ears 23 Cardiac disorders Arrhythmias 23 Eye disorders Visual disturbances 17 Ocular disorders 17 Renal and urinary disorders Renal insufficiency 11 1 Differentiation syndrome can be associated with other commonly reported events such as fever, leukocytosis, dyspnea, pneumonia, pleural effusion, pericardial effusion, hypotension, edema, weight gain, and renal failure. 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).

6.2 Postmarketing Experience 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.

AND PRECAUTIONS

• Patients Without t(15;17) Translocation or PML/RARα Fusion: Tretinoin capsules may be initiated based on morphological diagnosis of APL. Confirm diagnosis by detection of the t(15;17) translocation or PML/RARα fusion. ( 5.3 )
• Leukocytosis: Consider administering cytoreductive chemotherapy (including an anthracycline if not contraindicated or hydroxyurea) with tretinoin capsules in the setting of leukocytosis, as clinically indicated. ( 5.4 )
• Intracranial Hypertension: Tretinoin capsules have been associated with benign intracranial hypertension, especially in pediatric patients. Consider interruption, dose reduction, or discontinuation of tretinoin capsules as appropriate. ( 5.5 )
• Lipid Abnormalities: Patients experienced hypercholesterolemia and/or hypertriglyceridemia, which may be reversible upon completion of treatment. Monitor fasting triglycerides and cholesterol at baseline and periodically during treatment. ( 5.6 )
• Hepatotoxicity: Monitor liver function test results at baseline and during treatment as clinically indicated. ( 5.7 )
• Thromboembolic Events: Venous and arterial events have been reported; these events may occur during the first month of treatment with tretinoin capsules. ( 5.8 , 7.4 )

5.1 Embryo-Fetal Toxicity 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span> .

5.2 Differentiation Syndrome Differentiation Syndrome, which may be life-threatening or fatal, occurred in about 26% of patients with APL who received tretinoin capsules <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> .

5.3 Patients Without t(15;17) Translocation or PML/RARα Fusion 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 are not recommended for use in patients without these genetic markers <span class="opacity-50 text-xs">[see Indications and Usage ( 1 )]</span> .

5.4 Leukocytosis Rapidly evolving leukocytosis, which can be life-threatening, occurred in about 40% of patients with APL who received tretinoin capsules <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Patients who present with a baseline white blood cell count (WBC) &gt; 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.

5.5 Intracranial Hypertension 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.2 )]</span> .

5.6 Lipid Abnormalities 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.

5.7 Hepatotoxicity 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.

5.8 Thromboembolic Events Venous and arterial thromboembolic events, including cerebrovascular accident, myocardial infarction and renal infarct have been reported with tretinoin capsules <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span>. 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.4 )]</span> .

5.1 Embryo-Fetal Toxicity 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span> .

5.2 Differentiation Syndrome Differentiation Syndrome, which may be life-threatening or fatal, occurred in about 26% of patients with APL who received tretinoin capsules <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> .

5.3 Patients Without t(15;17) Translocation or PML/RARα Fusion 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 are not recommended for use in patients without these genetic markers <span class="opacity-50 text-xs">[see Indications and Usage ( 1 )]</span> .

5.4 Leukocytosis Rapidly evolving leukocytosis, which can be life-threatening, occurred in about 40% of patients with APL who received tretinoin capsules <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Patients who present with a baseline white blood cell count (WBC) &gt; 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.

5.5 Intracranial Hypertension 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.2 )]</span> .

5.6 Lipid Abnormalities 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.

5.8 Thromboembolic Events Venous and arterial thromboembolic events, including cerebrovascular accident, myocardial infarction and renal infarct have been reported with tretinoin capsules <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span>. 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.4 )]</span> .

PRECAUTIONS General: RENOVA (tretinoin cream) 0.02% should be used only as an adjunct to a comprehensive skin care and sunlight avoidance program (see INDICATIONS AND USAGE ). If a drug sensitivity, chemical irritation, or a systemic adverse reaction develops, use of RENOVA (tretinoin cream) 0.02% should be discontinued. Weather extremes, such as wind or cold, may be more irritating to patients using tretinoin-containing products. Information for Patients: RENOVA (tretinoin cream) 0.02% is to be used as described below unless otherwise directed by your physician: It is for use on the face. Avoid contact with the eyes, ears, nostrils, angles of the nose, and mouth. RENOVA (tretinoin cream) 0.02% may cause severe redness, itching, burning, stinging, and peeling if used on these areas. In the evening, gently wash your face with a mild soap. Pat skin dry and wait 20 to 30 minutes before applying RENOVA (tretinoin cream) 0.02%. Apply only a small pearl-sized (about ¼ inch or 5 mm diameter) amount of RENOVA (tretinoin cream) 0.02% to your face at one time. This should be enough to cover the entire affected area lightly. Do not wash your face for at least 1 hour after applying RENOVA (tretinoin cream) 0.02%. For best results, you are advised not to apply another skin care product or cosmetic for at least 1 hour after applying RENOVA (tretinoin cream) 0.02%. In the morning, apply a moisturizing sunscreen, SPF 15 or greater. RENOVA (tretinoin cream) 0.02% is a serious medication. Do not use RENOVA (tretinoin cream) 0.02% if you are pregnant or attempting to become pregnant. If you become pregnant while using RENOVA (tretinoin cream) 0.02%, please contact your physician immediately. Avoid sunlight and other medicines that may increase your sensitivity to sunlight. RENOVA (tretinoin cream) 0.02% does not remove wrinkles or repair sun-damaged skin. Please refer to the Patient Package Insert for additional patient information.

Drug

Interactions: Concomitant topical medications, medicated or abrasive soaps, shampoos, cleansers, cosmetics with a strong drying effect, products with high concentrations of alcohol, astringents, spices or lime, permanent wave solutions, electrolysis, hair depilatories or waxes, and products that may irritate the skin should be used with caution in patients being treated with RENOVA (tretinoin cream) 0.02% because they may increase irritation with RENOVA (tretinoin cream) 0.02%. RENOVA (tretinoin cream) 0.02% should not be administered if the patient is also taking drugs known to be photosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of the possibility of augmented phototoxicity. Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. These concentrations are near the tretinoin concentration of this clinical formulation (0.02%). A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day. These doses are 10 and 20 times the maximum human systemic dose, when adjusted for total body surface area. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.5 times the maximum human systemic dose, adjusted for total body surface area). For purposes of comparisons of the animal exposure to systemic human exposure, the maximum human systemic dose is defined as 1 gram of RENOVA (tretinoin cream) 0.02% applied daily to a 50 kg person (0.004 mg tretinoin/kg body weight). Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources. The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative. In dermal Segment I fertility studies in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (20 times the maximum human systemic dose adjusted for total body surface area), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day (10 times the maximum human systemic dose adjusted for total body surface area) and above were observed. A dermal Segment III study with RENOVA (tretinoin cream) 0.02% has not been performed in any species. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (83 times the human topical dose adjusted for total body surface area). Pregnancy: Teratogenic Effects ORAL tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters, and subhuman primates. It was teratogenic and fetotoxic in Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (42 times the maximum human systemic dose normalized for total body surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which, metabolically, is closer to humans for tretinoin than the other species examined, fetal malformations were reported at doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (417 times the maximum human systemic dose adjusted for total body surface area), although increased skeletal variations were observed at all doses. A dose-related increase in embryolethality and abortion was reported. Similar results have also been reported in pigtail macaques. TOPICAL tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (42 times the maximum human systemic dose adjusted for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day was dermally applied. There are other reports in New Zealand White rabbits administered doses of greater than 0.2 mg/kg/day (17 times the maximum human systemic dose adjusted for total body surface area) of an increased incidence of domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species. In contrast, several well-controlled animal studies have shown that dermally applied tretinoin may be fetotoxic, but not overtly teratogenic, in rats and rabbits at doses of 1.0 and 0.5 mg/kg/day, respectively (42 times the maximum human systemic dose adjusted for total body surface area in both species). With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of another formulation of topical tretinoin (Retin-A ® ). Although no definite pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known. Non-teratogenic Effects Dermal tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (42 times the maximum human systemic dose normalized for total body surface area). Oral tretinoin has been shown to be fetotoxic, resulting in skeletal variations and increased intrauterine death, in rats when administered 2.5 mg/kg/day (104 times the maximum human systemic dose adjusted for total body surface area). There are, however, no adequate and well-controlled studies in pregnant women. RENOVA (tretinoin cream) 0.02% should not be used during pregnancy.

Nursing

Mothers: It is not known whether this drug is excreted in human milk. Since many drugs are excreted in human milk, mitigation of fine facial wrinkles with RENOVA (tretinoin cream) 0.02% may be postponed in nursing mothers until after completion of the nursing period.

Pediatric

Use: Safety and effectiveness in patients less than 18 years of age have not been established.

Geriatric

Use: In clinical studies with RENOVA (tretinoin cream) 0.02%, patients aged 65 to 71 did not demonstrate a significant difference for improvement in fine wrinkling when compared to patients under the age of 65. Patients aged 65 and over may demonstrate slightly more irritation, although the differences were not statistically significant in the clinical studies for RENOVA (tretinoin cream) 0.02%. Safety and effectiveness of RENOVA (tretinoin cream) 0.02% in individuals older than 71 years of age have not been established.

INTERACTIONS

• Strong CYP3A Inhibitors and Inducers: Avoid coadministration with strong CYP3A inhibitors and inducers. ( 7.1 )
• Concomitant Use of Products Known to Cause Intracranial Hypertension : Avoid concomitant use with other products that can cause intracranial hypertension. ( 7.2 )
• Vitamin A : Avoid concomitant use with vitamin A. ( 7.3 )
• Anti-fibrinolytic Agents : Avoid concomitant use with anti-fibrinolytic agents. ( 7.4 )

7.1 Effects of Other Drugs on Tretinoin Capsules Strong or moderate CYP3A Inhibitors Avoid concomitant use of tretinoin capsules with strong CYP3A inhibitors if possible and monitor more frequently if concomitant use is unavoidable. Monitor patients taking moderate CYP3A inhibitors concomitantly with tretinoin capsules more frequently for adverse reactions. Tretinoin is a CYP3A substrate. Concomitant use with a strong CYP3A4 inhibitor increases tretinoin plasma concentrations, which may increase the risk of adverse reactions <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. Strong CYP3A Inducers Concomitant use of tretinoin capsules with strong CYP3A4 inducers may decrease tretinoin plasma concentrations, which may reduce its efficacy. Avoid concomitant use with strong CYP3A inducers if possible.

7.2 Concomitant Use of Products Known to Cause Intracranial Hypertension 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.5 )]</span> .

7.3 Vitamin A 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.

7.4 Anti-fibrinolytic Agents 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.8 )]</span>.

7.1 Effects of Other Drugs on Tretinoin Capsules Strong or moderate CYP3A Inhibitors Avoid concomitant use of tretinoin capsules with strong CYP3A inhibitors if possible and monitor more frequently if concomitant use is unavoidable. Monitor patients taking moderate CYP3A inhibitors concomitantly with tretinoin capsules more frequently for adverse reactions. Tretinoin is a CYP3A substrate. Concomitant use with a strong CYP3A4 inhibitor increases tretinoin plasma concentrations, which may increase the risk of adverse reactions <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. Strong CYP3A Inducers Concomitant use of tretinoin capsules with strong CYP3A4 inducers may decrease tretinoin plasma concentrations, which may reduce its efficacy. Avoid concomitant use with strong CYP3A inducers if possible.

7.2 Concomitant Use of Products Known to Cause Intracranial Hypertension 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.5 )]</span> .

7.3 Vitamin A 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.

7.4 Anti-fibrinolytic Agents 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.8 )]</span>.