Mirin 100

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MIRIN 50 (MYRIN® 50) MIRIN 100 (MYRIN® 100)

Composition:

Active substance: thalidomide;

1 tablet contains 50 mg or 100 mg of thalidomide;

Excipients:

Tablets of 50 mg: lactose monohydrate, copovidone, talc, magnesium stearate, microcrystalline cellulose, kaolin, sucrose, acacia, calcium carbonate, titanium dioxide (E 171), povidone, colloidal anhydrous silicon dioxide, sodium carboxymethylcellulose, quinoline yellow (E 104), glycerin;

Tablets of 100 mg: lactose monohydrate, copovidone, talc, magnesium stearate, microcrystalline cellulose, kaolin, sucrose, acacia, calcium carbonate, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Tablets of 50 mg: round, dome-shaped, yellow film-coated tablets;

Tablets of 100 mg: round, dome-shaped, white film-coated tablets.

Pharmacotherapeutic group.

Immunosuppressants. ATC code L04A X02.

Pharmacological Properties.

Pharmacodynamics.

The mechanism of action of thalidomide in patients with multiple myeloma is very diverse and not fully characterized. The known teratogenic effect is due to the antiangiogenic properties of thalidomide resulting from inhibition of vascular endothelial growth factor (VEGF) and fibroblast growth factor β.

In patients with multiple myeloma, the drug exerts immunomodulatory and anti-inflammatory effects and demonstrates potential antineoplastic activity. The mechanism of action is associated with inhibition of angiogenesis and production of tumor necrosis factor (TNF-α), reduction in modulation of adhesion molecules on the surface of individual cells (ICAM-1, VCAM-1, and E-selectin) involved in leukocyte migration, stimulation of naïve T-cells (causing proliferation, cytokine synthesis, and cytotoxicity), shift in the ratio of helper to cytotoxic T-cells, and inhibition of interleukin-12 production. The drug’s action is also associated with increased levels of interleukin-2 and γ-interferon, and decreased phagocytic activity of polymorphonuclear leukocytes.

Pharmacokinetics.

Absorption.

After single oral administration, thalidomide is slowly absorbed from the gastrointestinal tract. Maximum concentration, ranging from 1.15 to 3.47 µg/mL, is reached within 2.5 to 4.4 hours. Studies have shown that thalidomide at a dose of 200 mg follows a one-compartment pharmacokinetic model with first-order absorption and elimination rate constants.

Low solubility in the gastrointestinal tract may reduce the absorption rate of high doses of thalidomide. Thus, the absorption rate may be dose-dependent.

Concomitant administration of thalidomide with a high-fat meal results in only minor changes in the area under the plasma concentration-time curve (AUC) and maximum plasma concentration, although the time to peak concentration increases (to approximately 6 hours). This is due to delayed gastric emptying caused by fatty food. Food has a negligible effect on the extent of absorption of thalidomide in tablet form.

Distribution.

The volume of distribution reported in studies is approximately 1 L/kg of body weight. The mean plasma protein binding is 55% (R-isomer) and 66% (S-isomer).

Plasma distribution ratios are 0.86 and 0.95, respectively.

Thalidomide has been detected in human semen.

Metabolism.

Thalidomide undergoes no significant biotransformation in the liver and is primarily subject to non-enzymatic hydrolysis in plasma, forming multiple metabolites. Hydrolysis in the body occurs uniformly.

Elimination.

The mean elimination half-life of thalidomide ranges from 5.5 to 7.3 hours, depending on the daily dose administered. A small amount is excreted in urine—less than 1% of the total dose within 24 hours—with a renal clearance of 0.08 L/h; the remainder, approximately 6.4–10.4 L/h, is eliminated by other routes.

Most metabolites formed via spontaneous hydrolysis are excreted in urine. In clinical studies, the pharmacokinetics of thalidomide in patients with impaired renal function were similar to those in patients with normal renal function.

Clinical characteristics.

Indications.

Multiple myeloma, in cases of ineffectiveness of standard therapy.

Contraindications.

Hypersensitivity to the components of the drug.

Severe neutropenia (neutrophil count < 0.75×10⁹/L).

History of toxic epidermal necrolysis (TEN), Stevens–Johnson syndrome, or exfoliative dermatitis, since thalidomide may cause such conditions.

Thalidomide is contraindicated in women of reproductive age who do not use or are unable to use adequate contraceptive measures, as well as in women of reproductive age who may be treated with less toxic drugs.

Thalidomide is contraindicated in men who do not use adequate contraceptive measures (latex condom).

Interaction with other medicinal products and other forms of interaction.

Thalidomide enhances the sedative effect of barbiturates, alcohol, chlorpromazine, and reserpine; it also enhances the effects of opioid analgesics, benzodiazepines, and other anxiolytics, hypnotics, antidepressants with sedative effect, neuroleptics, antihistamines with sedative effect, centrally-acting antihypertensive agents, and baclofen.

The risk of peripheral neuropathy increases when thalidomide is used concomitantly with zalcitabine, vincristine, stavudine, or didanosine.

The risk of thrombosis and thromboembolic complications increases when thalidomide is used concomitantly with doxorubicin.

Repeated combinations of thalidomide with glucocorticoids (dexamethasone) and cytotoxic agents (cisplatin, cyclophosphamide, doxorubicin, and etoposide) increase the risk of deep vein thrombosis.

Concomitant use of thalidomide with oral contraceptives containing ethinylestradiol or norethindrone does not alter thalidomide blood concentrations.

Pharmacokinetic profiles of norethindrone and ethinylestradiol were studied in 10 healthy women after administration of a single dose containing 1 mg norethindrone acetate and 0.75 mg ethinylestradiol. Results were similar both during combination therapy and thalidomide monotherapy at steady-state concentrations of 200 mg per day.

Concomitant use of cytochrome P450-inducing agents such as lopinavir, nevirapine, efavirenz, griseofulvin, rifampicin, rifabutin, phenytoin, or carbamazepine with hormonal contraceptives may reduce the efficacy of contraceptive methods. Therefore, women of reproductive age requiring treatment with one or more of these agents should use two additional effective contraceptive methods.

Special precautions for use.

Women of childbearing potential must undergo a pregnancy test (minimum sensitivity 50 mIU/mL) before starting thalidomide therapy. The test must be performed within 24 hours prior to initiating treatment. Thalidomide must not be prescribed to women of childbearing potential until a negative pregnancy test result has been confirmed.

Pregnancy tests should be performed if a patient misses a dose of her contraceptive method or if any menstrual cycle irregularities occur.

Any suspicion of embryotoxic effects during Mirin treatment must be reported to the local drug regulatory authority or the Marketing Authorization Holder/Manufacturer representative. The patient should be immediately referred to a physician for further evaluation and consultation regarding reproductive toxicity.

Special precautions for HIV-infected patients.

Recent clinical studies have shown that thalidomide may increase viral load in HIV-infected patients undergoing long-term therapy. These patients should be monitored regularly. Zalcitabine, didanosine, and stavudine may increase the risk and severity of peripheral neuropathy due to enhanced adverse effects (see section "Adverse reactions"). Clinical monitoring is recommended.

Contraception must be used for at least 4 weeks prior to starting the drug, throughout the entire treatment period, and for at least 12 weeks after discontinuation of therapy. It should be noted that protease inhibitors, griseofulvin, rifampicin, rifabutin, phenytoin, and carbamazepine may reduce the effectiveness of hormonal contraceptives when used concomitantly; therefore, more reliable contraceptive methods should be used during thalidomide treatment in these cases.

Thalidomide is present in semen of men. Therefore, men taking Mirin must always use latex condoms during sexual contact with women of childbearing potential.

Blood and semen donation is prohibited during treatment and for 12 weeks after thalidomide therapy.

Alcoholic beverages must not be consumed during Mirin treatment.

Thalidomide may cause drowsiness, somnolence, and sedative effects. The sedative effect of thalidomide is enhanced when used concomitantly with alcohol. Patients should not take any medications that may cause drowsiness without prior consultation with their physician.

Peripheral neuropathy is a potentially serious adverse effect associated with thalidomide therapy (see section "Adverse reactions"). Adverse effects usually resolve after dose reduction or discontinuation of the drug. In some cases, peripheral neuropathy may be irreversible, especially after prolonged use of high doses. If long-term thalidomide therapy is planned, baseline nerve function should be assessed and monitored for at least 6 months. If such monitoring is not feasible, regular clinical examinations are required.

Patients must inform their physician if they experience tingling, numbness, or paresthesia. Additionally, patients should be regularly questioned about symptoms of peripheral neuropathy (numbness, tingling, or pain in hands and feet). Any symptoms of peripheral neuropathy should be documented.

If thalidomide-induced neuropathy is confirmed during or after treatment, further use of Mirin should be restricted. Medications known to be associated with neuropathy should be used with caution in patients receiving thalidomide (e.g., zalcitabine, didanosine, and stavudine) (see section "Interaction with other medicinal products and other forms of interaction").

Mirin may potentially worsen pre-existing neuropathy and therefore should not be used in patients with clinical signs of peripheral neuropathy unless the expected benefit outweighs the potential risk.

A causal relationship between thalidomide and epileptic seizures is suspected. Patients with a history of seizures or those predisposed to seizures require careful clinical monitoring during thalidomide therapy to prevent acute epileptic episodes.

Venous thromboembolism is a major complication in oncological diseases. The risk of deep vein thrombosis or pulmonary embolism is increased in patients receiving thalidomide, especially when used in combination with chemotherapy and/or dexamethasone.

Patients at risk of thrombosis and those receiving thalidomide in combination with chemotherapy and/or dexamethasone should be prescribed low-dose anticoagulants.

Cases of neutropenia have been reported during thalidomide use. Treatment should not be initiated in patients with an absolute neutrophil count below 0.75×10⁹/L (see section "Contraindications"). Continued monitoring is recommended in patients predisposed to neutropenia.

Thalidomide is not used in patients with toxic epidermal necrolysis (TEN) as emergency therapy for severe drug eruptions. In placebo-controlled trials, patients with previously diagnosed TEN who received thalidomide showed increased mortality. One case of thalidomide-induced TEN has been reported.

Mirin should be taken only under medical prescription and supervision by a physician experienced in the use of thalidomide.

Use during pregnancy or breastfeeding.

Thalidomide is contraindicated during pregnancy.

Thalidomide is known to cause teratogenic effects, including severe congenital malformations and intrauterine fetal death. A single dose taken during pregnancy may result in severe fetal developmental abnormalities. Severe fetal malformations have been observed in approximately 30% of pregnant women who took this drug. These include: ectromelia (amelia, phocomelia, hemimelia) of upper and/or lower limbs, microtia with developmental abnormalities of the external auditory canal (obstructed or absent), involvement of the middle and inner ear (rare), eye abnormalities (anophthalmia, microphthalmia), congenital heart defects, and kidney dysfunction. Other less frequently reported abnormalities have also been described.

The risk of severe congenital defects, particularly phocomelia or fetal death, is extremely high during the critical period of pregnancy (from 35 to 50 days after the last menstrual period). The risk of potentially severe congenital defects during other periods of pregnancy is unknown but may be significant. Therefore, based on the above data, thalidomide use at any stage of pregnancy is contraindicated.

If a patient becomes pregnant while taking thalidomide despite using contraceptive measures, there is a high risk of severe fetal malformations or fetal death.

If a patient or her partner fails to take preventive measures, or if the patient experiences menstrual cycle irregularities or suspects pregnancy, a pregnancy test should be performed or medical advice should be sought.

If a patient becomes pregnant during thalidomide treatment, the drug must be discontinued immediately.

The patient or her partner should consult a physician for further safety evaluation and teratology consultation.

Thalidomide is contraindicated during breastfeeding. It is unknown whether thalidomide is excreted in breast milk.

Effect on ability to drive and use machines.

Patients taking thalidomide should refrain from driving vehicles or operating potentially hazardous machinery.

Dosage and Administration

The tablets are intended for oral use. It is recommended to take the medication at bedtime due to its sedative effect. The initial dose for adults is 200 mg per day, with weekly increments of 100 mg until the maximum daily dose of 800 mg is reached, depending on the patient's tolerance. However, due to the drug's toxicity, the average dose usually remains below 400 mg per day. Depending on tolerance, toxicity, and efficacy, lower maintenance doses (25–100 mg per day) may be used. To achieve the required dosage, tablets with the appropriate content of the active substance should be selected.

Patients with Renal or Hepatic Impairment

There are no data regarding use in patients with hepatic insufficiency. These patients should receive the drug with caution and under strict medical supervision due to the potential risk of toxicity.

Clinical studies conducted in patients with renal impairment have shown that dose adjustment is not required. However, as with patients with hepatic insufficiency, careful monitoring is necessary.

Children

Not applicable.

Overdose

High doses of thalidomide do not cause ataxia or respiratory depression, and there are no reports of fatal outcomes at doses up to 14.4 g.

Side effects

Peripheral neuropathy is a potentially serious adverse effect. Usually, adverse effects resolve after dose reduction or discontinuation of treatment with the drug. In some cases, peripheral neuropathy may be irreversible, for example, after administration of high doses over a prolonged period.

The following adverse reactions may occur during treatment with thalidomide:

Infections and infestations: bronchitis, fungal dermatitis, infections, oral candidiasis, pharyngitis, rhinitis, sinusitis;

Benign, malignant and unspecified neoplasms (including cysts and polyps): tumor lysis syndrome;

Blood and lymphatic system disorders: anemia, eosinophilia, hemolytic uremic syndrome, leukopenia, lymphadenopathy, neutropenia, thrombocytopenia, thrombotic microangiopathy;

Immune system disorders: hypersensitivity reactions;

Endocrine disorders: hypothyroidism;

Metabolism and nutrition disorders: anorexia, hyperglycemia, hyperlipidemia, hypoglycemia, fluid retention, increased appetite;

Psychiatric disorders: agitation, confusion, depression, decreased libido, insomnia, mood changes, nervousness;

Nervous system disorders: paresthesia, headache, tremor, somnolence, dizziness, epilepsy, hyperesthesia, carpal tunnel syndrome, impaired coordination, lethargy, ataxia, neuropathy, numbness in legs, sedative effect, paroxysm, syncope, vasovagal syncope, tremor, dysesthesia, cerebrovascular events;

Eye disorders: photophobia, decreased vision, vision loss;

Ear and labyrinth disorders: hearing loss, deafness, tinnitus, vertigo;

Cardiac disorders: bradycardia, tachycardia, arrhythmia, venous thrombosis, orthostatic hypotension, thromboembolic complications, arterial thrombosis, angina pectoris, ventricular fibrillation, cardiovascular disorders, chronic heart failure, myocardial infarction, palpitations, pericarditis, pleuropericarditis, deep vein thrombosis, atrial fibrillation;

Respiratory, thoracic and mediastinal disorders: bronchospasm, dyspnea, nasal congestion, pulmonary embolism, respiratory distress, pneumonia, interstitial lung disease, bronchopneumopathy;

Gastrointestinal disorders: abdominal pain, constipation, diarrhea, dry mouth, flatulence, intestinal obstruction, nausea, parotid gland hypertrophy, vomiting, toothache, dry mouth, gastrointestinal perforation, diverticular perforation, peritonitis;

Skin and subcutaneous tissue disorders: acne, alopecia, dry skin, erythema, exanthema, exfoliative dermatitis, nail disorders, lichenoid oral lesions, vesicular rash, pruritus, rash, maculopapular rash, maculopapular exanthema, bullous skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, photosensitization, increased sweating, skin edema, acute generalized exanthematous pustulosis, urticaria, hyperemia, urticaria, photosensitization;

Musculoskeletal and connective tissue disorders: aseptic necrosis, back pain, bone pain, leg cramps, muscle weakness, myalgia, neck pain, neck muscle rigidity;

Renal and urinary disorders: albuminuria, hematuria, renal failure, transient oliguria, urinary incontinence;

Reproductive system and breast disorders: impotence, decreased ovarian function, menstrual cycle disturbances, secondary amenorrhea;

Congenital, familial and genetic disorders: teratogenicity (e.g., congenital malformations, phocomelia);

Blood disorders: thrombotic thrombocytopenic purpura, lymphopenia, pancytopenia;

General disorders and administration site conditions: asthenia, chest pain, chills, peripheral edema, facial edema, fatigue, fever, malaise, pain, peripheral edema, tachyphylaxis, weakness, bacterial meningitis;

Investigations: false-positive liver function test, increased liver enzyme activity, elevated aspartate aminotransferase levels, increased body weight, elevated blood amylase levels, elevated triglyceride levels, increased concentration of immunodeficiency virus in blood, abnormal liver function test results.

Shelf life.

3 years.

Storage conditions.

Store at 15–30 °C.

Keep out of reach of children.

Packaging.

10 tablets in a blister; 3 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LIPOMED AG.

Manufacturer's address and place of business.

4144 Arlesheim, Fabrikmatte 4, Switzerland.