Tretinoin

Tretinoin is an Retinoic Acid Derivative belonging to pharmacology class of Anti-Acne agent.

Tretinoin can be used in the treatment of Acne vulgaris, Palliation of fine wrinkles, mottled hyperpigmentation, and facial skin roughness

Tretinoin is Well absorbed from the gastrointestinal tract (oral); minimally absorbed from the skin (topical). Enhanced absorption with food (oral). Bioavailability: Approx 50% (oral). Time to peak plasma concentration: 1-2 hours (oral).Plasma protein binding: >95%, mainly to albumin and get Metabolized in the liver by CYP450 enzymes to form 4-oxo-trans-retinoic acid (primary metabolite); displays auto-metabolism and gets excreted Via urine (63%); faeces (30%). Terminal elimination half-life: 0.5-2 hours

The common side effects associated with Tretinoin include Venous thrombosis, MI, pseudotumor cerebri/benign intracranial hypertension (children), hypercholesterolemia or hypertriglyceridemia (reversible), hypercalcemia, psychiatric disorders (e.g. depression, anxiety, mood alterations), elevated LFT.

Tretinoin is available in the form of Cream, gel, lotion, Capsule.

The molecule is available in India, USA, Japan, Germany.

Tretinoin is a derivative of vitamin A. When used topically, it modifies epithelial growth and differentiation. In patients with acne, it decreases the cohesiveness of follicular epithelial cells and decreases microcomedone formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones.

The onset of action for Tretinoin : Acne: ≥2 weeks, may take ≥7 weeks; Facial wrinkles: Up to 6 months.

Tretinoin is available in Cream, gel, lotion, Capsule.

Administer with food, preferably with the main meal of the day.

Tretinoin can be used in the treatment of Acne vulgaris and palliation of fine wrinkles.

Tretinoin appears to bind one or more nuclear receptors and decreases proliferation and induces differentiation of APL cells; initially produces maturation of primitive promyelocytes and repopulates the marrow and peripheral blood with normal hematopoietic cells to achieve complete remission.

Tretinoin is approved for use in the following clinical indications

Acne vulgaris: Altreno, Atralin, Avita, Retin-A, Retin-A Micro, Stieva-A [Canadian product], Tretin-X, Vitamin-A Acid [Canadian product]: Treatment of acne vulgaris.

Palliation of fine wrinkles: Renova: Adjunctive treatment for mitigation (palliation) of fine wrinkles in patients who use comprehensive skin care and sun avoidance programs.

Palliation of fine wrinkles, mottled hyperpigmentation, and facial skin roughness: Refissa: Adjunctive treatment for mitigation (palliation) of fine wrinkles, mottled hyperpigmentation, and tactile roughness of facial skin in patients who do not achieve such palliation using comprehensive skin care and sun avoidance programs alone.

Acute promyelocytic leukemia (remission induction): Induction of remission in patients with acute promyelocytic leukemia, French American British (FAB) classification M3 (including the M3 variant) characterized by t(15;17) translocation and/or PML/RARα gene presence

Although not approved there have been certain off labelled uses documented for Tretinoin which includes:

Acute promyelocytic leukemia (consolidation therapy); Acute promyelocytic leukemia (maintenance therapy in high-risk patients).

Acne vulgaris: Topical: Apply to acne lesions once daily before bedtime or in the evening. Consider starting with the lowest possible concentration to minimize skin irritation and increase potency as tolerated. For moderate to severe acne, may be used as part of an appropriate combination regimen. Avoid simultaneous application with benzoyl peroxide (may reduce tretinoin efficacy) .

Palliation of fine wrinkles (Refissa/Renova), mottled hyperpigmentation, and tactile roughness of facial skin (Refissa): Topical: Apply a pea-sized amount of cream to entire face once daily in the evening or before bedtime.

• Acute promyelocytic leukemia:
• Remission induction: Note: For non–high-risk APL patients (WBC ≤10,000/mm³), induction therapy consists of tretinoin with arsenic trioxide, although tretinoin with anthracycline-based chemotherapy is an option when arsenic trioxide cannot be used. For patients with high-risk APL (WBC >10,000/mm³), induction therapy generally consists of tretinoin and anthracycline-based chemotherapy ± arsenic trioxide.
• Manufacturer's labeling: Oral: 45 mg/m²/day in 2 equally divided doses until documentation of complete remission (CR); discontinue 30 days after CR or after 90 days of treatment, whichever occurs first.
• Tretinoin with arsenic trioxide: Oral: 45 mg/m²/day in 2 equally divided doses until <5% blasts in marrow and no abnormal promyelocytes or complete remission, up to a maximum of 60 or 85 days; refer to protocol(s) for further information .
• Tretinoin with idarubicin: Oral: 45 mg/m²/day in 2 equally divided doses until complete hematologic remission.
• Tretinoin with daunorubicin and cytarabine: Oral: 45 mg/m²/day in 2 equally divided doses until complete remission or 90 days (Powell 2010) or until complete hematologic remission.
• Tretinoin with arsenic trioxide and gemtuzumab ozogamicin: Oral: 45 mg/m²/day in 2 equally divided doses until <5% blasts in marrow and no abnormal promyelocytes .
• Tretinoin with gemtuzumab ozogamicin: Oral: 45 mg/m²/day in 2 equally divided doses until complete remission.
• Consolidation therapy (off-label use):
• Tretinoin with arsenic trioxide: Oral: 45 mg/m²/day in 2 equally divided doses days 1 to 14 every 28 days for 7 cycles or for 2 weeks every 28 days for 7 cycles .
• Tretinoin with idarubicin/mitoxantrone: Oral: 45 mg/m²/day in 2 equally divided doses for 15 days each month for 3 months (in combination with idarubicin [courses 1 and 3] and mitoxantrone [course 2]) .
• Tretinoin and daunorubicin after arsenic trioxide: Oral: 45 mg/m²/day in 2 equally divided doses for 7 days of each cycle (in combination with daunorubicin for 2 cycles; begin after 2 arsenic trioxide consolidation cycles).
• Maintenance therapy (off-label use): Oral: 45 mg/m²/day in 2 equally divided doses for 15 days every 3 months (in combination with mercaptopurine and methotrexate) for 2 years or 45 mg/m²/day in 2 equally divided doses for 7 days every other week (± mercaptopurine and methotrexate) for 1 year. Note: For non–high-risk patients (WBC ≤10,000/mm³) receiving chemotherapy-free therapy, maintenance therapy is not needed.

Cream, gel, lotion, Capsule

10 mg,0.025%, 0.05%, 0.02%,0.04%, 0.06%,0.08%,0.01%.

Cream, gel, lotion, Capsule

• Dose Adjustment in Hepatic Patient:

Hepatotoxicity during treatment: Liver function tests >5 × ULN: Consider temporarily withholding treatment. Most liver function test abnormalities will resolve without interruption of treatment or after completion of tretinoin therapy.

• Dose Adjustment in Pediatric Patient:

Acne vulgaris: Children ≥8 years and Adolescents: Topical: Apply to affected areas once daily. Begin therapy with a weaker formulation of tretinoin and increase the concentration as tolerated; if stinging or irritation develop, decrease frequency of application. Approved ages varies by product; see individual product labeling. Guidelines suggest that topical retinoids may be used as part of a therapeutic regimen for all types and severity of acne in children and adolescents; however, specific data for each tretinoin product formulation may not be available.

Absorption of retinoids has been shown to be enhanced when taken with food.

Management: Administer with food.

Tretinoin may be contraindicated in the following conditions:

Hypersensitivity to tretinoin or any component of the formulation.

Concerns related to adverse effects:

Fish allergies: Atralin gel contains soluble fish proteins; use caution in patients with sensitivities or allergies to fish.

Hypersensitivity reactions: Discontinue tretinoin if drug sensitivity, chemical irritation, or a systemic adverse reaction occurs.

Photosensitivity: Use is associated with increased susceptibility/sensitivity to UV light; avoid or minimize excessive exposure to sunlamps or sunlight. Daily sunscreen (SPF ≥15) use and other protective measures (eg, clothing over treated areas) are recommended. Use with caution in patients with personal or family history of skin cancer.

Skin irritation: Treatment can increase skin sensitivity to weather extremes of wind or cold. Excessive dryness, redness, and swollen or blistered skin may occur. Also, concomitant topical medications (eg, medicated or abrasive soaps, cleansers, or cosmetics with a strong drying effect) should be used with caution due to increased skin irritation. Depending on the severity of irritation, use a moisturizer, reduce the amount or frequency, or discontinue use until irritation disappears.

There is no sufficient scientific evidence traceable regarding use and safety of Tretinoin in concurrent use with alcohol.

It is not known if tretinoin is present in breast milk following topical application.

Tretinoin is an endogenous substance and likely present in breast milk. Although the manufacturer recommends caution when administering tretinoin (topical) to breastfeeding females, the use of topical agents is generally preferred over systemic agents for the treatment of facial acne in women who are breastfeeding; topical tretinoin may be compatible with breastfeeding; however, specific studies are not available. Avoid applying large amounts over prolonged periods of time to decrease the potential for systemic absorption . Mothers should wash hands following application. Because topical agents can be transferred to a breastfeeding infant, avoid direct skin-to-skin contact with treated areas. Use of alternative agents or postponement of therapy may also be considered. When used for other indications, treatment should be postponed until after breastfeeding is complete.

Pregnancy

Pregnancy Category (FDA): D

Oral tretinoin has been shown to be teratogenic in rats, mice, 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 (8 times the maximum human systemic dose adjusted 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 / kr / day(83 times the maximum human systemic dose adjusted for total body surface area), although skeletal variations were observed at all doses. A dose - related increase in embryolethality and abortion were reported. Similar results have been reported in pigtail macaques.

Topical tretinoin in animal teratogenecity tests have 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 (8 times e maximum human systemic dose adjusted for total body surface area). Anomalies(humerous: short 13 % , bent 6 %, os parietal incompletely ossified 14 % ) have also been reported when 10 mg / kg / day was topically applied.

There are other reports in New Zealand White rabbits administered in doses of greater than 0.2 mg / kg / day ( 3.3 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 overly teratogenic in rats and rabbits at doses of 1.0 and 0.5 mg / kg / day, respectively (8 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 tretinoin.

Although no definite pattern of teratogenicity and no causal association has been established form these cases, five of the reports describe there are 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.

The adverse reactions related to Tretinoin can be categorized as

Common Adverse effects: Venous thrombosis, MI, pseudotumor cerebri/benign intracranial hypertension (children), hypercholesterolemia or hypertriglyceridemia (reversible), hypercalcemia, psychiatric disorders (e.g. depression, anxiety, mood alterations), elevated LFT, Sweet’s

Less Common Adverse effects: Sweet's syndrome (acute febrile neutrophilic dermatosis); hypersensitivity reactions, photosensitivity (topical), skin irritation (e.g. excessive dryness, redness, swollen, blistered), application site reactions (e.g. feeling of warmth, dry skin, peeling, burning, stinging, pain). Blood and lymphatic system disorders: Thrombocytosis, basophilia.

Rare Adverse effects: Nasal dryness, asthma, respiratory failure.

The clinically relevant drug interactions of Tretinoin is briefly summarized here

Oral: May potentially alter pharmacokinetics with CYP450 inducers (e.g. rifampicin, glucocorticoids, phenobarbital, pentobarbital) and CYP450 inhibitors (e.g. ketoconazole, cimetidine, erythromycin, verapamil, diltiazem, ciclosporin). Topical: May increase risk of skin irritation with topical medications, medicated or abrasive soaps, shampoos, cleansers, permanent wave solutions, electrolysis, hair depilatories or waxes, cosmetics with strong drying effect, products with high concentrations of alcohol, astringents, spices or lime, and preparations containing sulfur, resorcinol, benzoyl peroxide or salicylic acid.

Potentially Fatal: Oral: Increased risk of pseudotumour cerebri/intracranial hypertension with tetracyclines. Increased risk of symptoms suggestive of hypervitaminosis A with other retinoids and vitamin A. Increased risk of thrombotic complications with antifibrinolytic agents (e.g. tranexamic acid, aminocaproic acid, aprotinin).

The common side of Tretinoin include the following

Venous thrombosis, MI, pseudotumor cerebri/benign intracranial hypertension (children), hypercholesterolemia or hypertriglyceridemia (reversible), hypercalcemia, psychiatric disorders (e.g. depression, anxiety, mood alterations), elevated LFT, Sweet’s.

Pregnancy

Pregnancy Category (FDA): D

Oral tretinoin has been shown to be teratogenic in rats, mice, 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 (8 times the maximum human systemic dose adjusted 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 / kr / day(83 times the maximum human systemic dose adjusted for total body surface area), although skeletal variations were observed at all doses. A dose - related increase in embryo lethality and abortion were reported. Similar results have been reported in pigtail macaques.

Topical tretinoin in animal teratogenecity tests have 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 (8 times e maximum human systemic dose adjusted for total body surface area). Anomalies(humorous: short 13 % , bent 6 %, os parietal incompletely ossified 14 % ) have also been reported when 10 mg / kg / day was topically applied.

There are other reports in New Zealand White rabbits administered in doses of greater than 0.2 mg / kg / day ( 3.3 times the maximum human systemic dose adjusted for total body surface area ) of an increased incidence of domed head and hydrocephaly, typical of reinoid - induced fetal malformations in this species.

In contrast, several well - controlled animal studies have shown that dermally applied tretinoin may be fetotoxic, but not overly teratogenic in rats and rabbits at doses of 1.0 and 0.5 mg / kg / day, respectively (8 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 reprots 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 tretinoin.

Although no definite pattern of teratogenecity and no causal association has been established form these cases, five of the reports describe therare 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.

Nonteratogenic Effects

Topical tretinoin has been shown to be ferotoxic in rabbits when administered 0.5 mg / kg /day (8 times the maximum human systemic dose adjusted for total body surface area). Oral tretinoin has been shown to be ferotoxic, resulting in skeletal variations and increased intrauterine death in rats when administered 2.5 mg / kg / day ( 20 mes the maximum human systemic dose adjusted for total body surface area).

Pregnancy Category (AUS):

Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tretinoin (topical) in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Tretinoin (topical) during labor and delivery.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tretinoin is used by a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 12 have not been established.

Geriatric Use

Safety and effectiveness in a geriatric populationhave not been established. Clinical studies of tretinoin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients.

Gender

There is no FDA guidance on the use of Tretinoin (topical) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Tretinoin (topical) with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Tretinoin (topical) in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Tretinoin (topical) in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Tretinoin (topical) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Tretinoin (topical) in patients who are immunocompromised.

Symptoms: Oral: Reversible signs of hypervitaminosis A (e.g. headache, nausea, vomiting, mucocutaneous symptoms), transient headache, facial flushing, cheilosis, abdominal pain, dizziness, and ataxia. Topical: Marked skin redness, peeling, blistering, or discomfort.

Management: Oral: Treat patient in a special haematological unit. Topical: Discontinue use and apply cold compress and a bland cream. If ingested, promote rapid gastric emptying by inducing emesis, gastric lavage and/or forced fluids.

Pharmacodynamics:

Tretinoin is a retinoid and an acid from of vitamin A. Topically, it modifies epithelial growth and differentiation; in acne treatment, it decreases the cohesiveness of follicular epithelial cells and microcomedo formation, stimulates mitotic activity, and increases the turnover of follicular epithelial cells resulting in the extrusion of comedones. Systemically, tretinoin specifically binds to 1 or more nuclear retinoic acid receptors (RAR), induces cellular differentiation, and decreases proliferation of acute promyelocytic leukemia (APL) cells.

Pharmacokinetics:

Absorption: Well absorbed from the gastrointestinal tract (oral); minimally absorbed from the skin (topical). Enhanced absorption with food (oral). Bioavailability: Approx 50% (oral). Time to peak plasma concentration: 1-2 hours (oral).

Distribution: Plasma protein binding: >95%, mainly to albumin.

Metabolism: Metabolised in the liver by CYP450 enzymes to form 4-oxo-trans-retinoic acid (primary metabolite); displays auto-metabolism.

Excretion: Via urine (63%); faeces (30%). Terminal elimination half-life: 0.5-2 hours.

1. https://www.uptodate.com/contents/Tretinoin -drug-information?search=Tretinoin &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/Tretinoin _2015-1215.pdf
4. https://www.mims.com/india/drug/info/Tretinoin ?type=full&mtype=generic#mechanism-of-action