Vesanoid^® (Capsules) Instructions for Use

Marketing Authorization Holder

Cheplapharm Arzneimittel, GmbH (Germany)

Manufactured By

Catalent Germany Eberbach, GmbH (Germany)

Packaging and Quality Control Release

CENEXI (France)

ATC Code

L01XF01 (Tretinoin)

Active Substance

Tretinoin (Rec.INN registered by WHO)

Dosage Form

Vesanoid®

Capsules 10 mg: 100 pcs.

Dosage Form, Packaging, and Composition

Capsules soft gelatin, oval-shaped, length 8.8-11.2 mm, diameter 5.8-8.2 mm; one half of the capsule is orange-yellow, opaque; the other half is reddish-brown, opaque; capsule contents are a suspension from yellow to greenish-yellow.

Excipients: soybean oil, yellow beeswax, hydrogenated soybean oil, partially hydrogenated soybean oil.

Capsule shell composition[glycerol 85%, gelatin, Carion 83 (hydrolyzed potato starch, mannitol, sorbitol), titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172)].

100 pcs. – dark glass bottles (1) – cardboard packs^×.

^× with first-opening protection in the form of transparent polyethylene stickers located on the flaps and side panels

Clinical-Pharmacological Group

Antitumor drug. Retinoid

Pharmacotherapeutic Group

Antineoplastic agent

Pharmacological Action

Retinoid. Structurally similar to vitamin A, it is a natural metabolite of retinol. When taken orally, it suppresses the differentiation and growth of the clone of altered blood cells, including human myeloleukemic cells. The mechanism of action in acute promyelocytic leukemia is likely due to damage caused by the binding of tretinoin to nuclear retinoic acid receptors.

When applied topically, it enhances cell proliferation in the papillary layer of the skin, reduces the adhesion of cells involved in the formation of acne vulgaris. When treating open comedones, it helps to even out the skin surface without signs of inflammation. When treating closed comedones, it promotes their transition to open comedones or papules, which then heal without scarring after removal of the keratin plug. Prevents the formation of new comedones.

Pharmacokinetics

Tretinoin is a natural metabolite of retinol, which is normally present in plasma. After oral administration, Tretinoin is absorbed from the gastrointestinal tract. Plasma concentration returns to the initial endogenous level 7-12 hours after a single 40 mg dose.

Plasma protein binding is high. Does not accumulate.

T_1/2 is 0.7 hours. After oral administration of radioactively labeled tretinoin, about 60% is excreted in the urine and about 30% in the feces. Metabolites are formed by oxidation and glucuronidation.

With prolonged use of tretinoin, a decrease in its plasma concentration is observed, which may be due to the induction of CYP system isoenzymes.

Indications

For oral administration: acute promyelocytic leukemia (for induction of remission) both in patients who have not previously received therapy and in cases of relapse or refractoriness to standard therapy (daunorubicin or cytarabine).

For topical application: acne vulgaris (including with the formation of comedones, papules, pustules), confluent acne. Favre-Racouchot disease (nodular cystic elastosis of the skin with comedones).

ICD codes

Dosage Regimen

Administer the total daily dose as two divided doses, taken orally in the morning and evening.

For induction of remission in acute promyelocytic leukemia, the recommended dose is 45 mg/m²/day.

Calculate the dose using the patient’s body surface area.

Continue therapy for a minimum of 45 days and until complete remission is achieved.

Discontinue therapy 30 days after achieving complete remission or after 90 days of treatment, whichever occurs first.

Take capsules with a full glass of water. Do not chew or suck the capsules.

Take with or immediately after meals to improve gastrointestinal tolerance.

For patients experiencing severe or life-threatening adverse reactions, temporarily interrupt therapy.

Upon resolution of adverse reactions, resume treatment at a reduced dose of 25-35 mg/m²/day.

For patients with hepatic impairment, initiate therapy at a reduced dose.

For patients with renal impairment, initiate therapy at a reduced dose.

Monitor patients closely for signs of retinoic acid syndrome.

Initiate high-dose corticosteroid therapy immediately at the earliest signs of retinoic acid syndrome.

Monitor liver function tests, triglyceride, and cholesterol levels regularly during treatment.

Adverse Reactions

Retinoic acid syndrome often – fever, dyspnea, shortness of breath, acute respiratory distress syndrome, pulmonary infiltrate, hyperleukocytosis, arterial hypotension, pleural effusion, renal and hepatic failure.

Dermatological reactions possible xeroderma, rash, cheilitis; rarely – erythema, itching, increased sweating, cellulitis, alopecia, exfoliative dermatitis, dryness of mucous membranes, xerophthalmia.

From the digestive system possible dry mouth, nausea, vomiting, increased activity of liver transaminases; rarely – abdominal pain, diarrhea, constipation, bullous stomatitis.

From the CNS rarely – dizziness, impaired consciousness, increased intracranial pressure, anxiety, depression, visual and hearing disturbances.

From metabolism possible increase in plasma triglycerides, cholesterol, changes in body weight.

From the respiratory system rarely – cough, pleural effusion, swelling of the nasal mucosa, shortness of breath, pharyngitis, wheezing in the lungs, stridor breathing.

From the cardiovascular system rarely – arrhythmias.

From the musculoskeletal system rarely – muscle and bone pain.

From the hematopoietic system rarely – increased bleeding.

Other possible edema; rarely – fever, chills, addition of infections (including pneumonia, septicemia), general weakness and drowsiness, chest and back pain.

With topical application possible redness, burning sensation, peeling of the skin at the application site; in isolated cases – swelling, blistering or crusting, photosensitivity.

Contraindications

Hypersensitivity to tretinoin; pregnancy, breastfeeding period (for oral administration), history of skin epithelioma (including family history).

For topical application: acute inflammatory (including eczematous) skin lesions, wounds, burns.

Use in Pregnancy and Lactation

Contraindicated during pregnancy. Women of childbearing potential must use effective methods of contraception at least 1 month before starting treatment, during therapy, and for 1 month after discontinuation of tretinoin. Treatment should begin on the 2nd-3rd day of a normal menstrual cycle. Two weeks before starting treatment, the absence of pregnancy must be confirmed by laboratory tests. Such tests should be performed once a month.

If oral administration is necessary during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Should be used with caution in patients with hepatic insufficiency. The dose is reduced in this category of patients.

Use in Renal Impairment

Should be used with caution in patients with renal insufficiency. The dose is reduced in this category of patients.

Pediatric Use

Should be used with caution in children.

Special Precautions

Oral Tretinoin should only be prescribed by a physician experienced in the treatment of hematological/oncological diseases.

To prevent retinoic acid syndrome with a significant increase in the number of leukocytes or the appearance of other signs of this syndrome, full chemotherapy in adequate doses is prescribed. At the earliest signs, a course of treatment with dexamethasone should be started immediately.

When applied topically, avoid getting tretinoin into the eyes, mouth, mucous membranes; in case of contact, rinse immediately with water.

During treatment, it is recommended to avoid sun exposure. Treatment can be started on tanned skin after the tan has faded.

During the first week of treatment, an exacerbation of acne may occur.

Tretinoin should not be used simultaneously with drugs that cause skin desquamation, as well as with cosmetic and hygiene products that cause dryness and skin irritation.

Drug Interactions

Tretinoin is metabolized in the liver with the participation of CYP450 system isoenzymes. Therefore, when used concomitantly with drugs that affect these enzymes, a change in pharmacokinetic parameters cannot be excluded.

Tretinoin reduces the contraceptive effect of progestogens.

When used concomitantly with tetracyclines, an increase in intracranial pressure is possible.

When used concomitantly with vitamin A, symptoms of hypervitaminosis are observed.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.