Tarlige

Mirogabalin besilate.

Each film-coated tablet contains mirogabalin besilate equivalent to 2.5, 5, 10 and 15 mg of mirogabalin.
The debossed line for scoring is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
Excipients/Inactive Ingredients: Tablet core: D-mannitol, Microcrystalline cellulose, Carmellose calcium, Tocopherol, Magnesium aluminometasilicate, Citric acid hydrate, Magnesium stearate.
Tablet coating: Hypromellose, Titanium oxide, Talc, Yellow ferric oxide, Red ferric oxide.

Therapeutic group: ANALGESICS, Other analgesics and antipyretics. ATC Code: N02BG11.
PHARMACOLOGY: Pharmacodynamics: Mechanism of action: Mirogabalin is considered to exhibit its analgesic effect by reducing calcium current via binding to the α₂δ subunit, which plays an auxiliary role in functions of voltage-gated calcium channels in the nervous system.
Pharmacodynamic effects: Mirogabalin increased the pain threshold to mechanical stimulation in partial sciatic nerve ligation model rats.
Mirogabalin increased the pain threshold to mechanical stimulation in streptozotocin-induced diabetic model rats.
Clinical efficacy and safety: 1. Phase 3 multinational clinical study: In a double-blind controlled study in 824 patients with diabetic peripheral neuropathic pain, each patient received 14-week treatment with mirogabalin 15 mg (5 mg/day for 1 week, 10 mg/day for 1 week, and then 15 mg/day for 12 weeks: total 14-week treatment), 20 mg (10 mg/day for 1 week and then 20 mg/day for 13 weeks: total 14-week treatment), or 30 mg (10 mg/day for 1 week, 20 mg/day for 1 week, and then 30 mg/day for 12 weeks: total 14-week treatment)^Note) or placebo. The mirogabalin 30 mg/day group showed statistically significant improvement in pain scores at Week 14, compared with the placebo group. (See Table 1.)

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The frequencies of adverse reactions were 18.8% (31/165 patients) in the 20-mg/day group and 36.4% (60/165) in the 30-mg/day group. Common adverse reactions in the 20-mg/day group included somnolence in 9.7% (16/165), dizziness in 7.9% (13/165), oedema peripheral in 1.8% (3/165), and weight gain in 1.8% (3/165); those in the 30-mg/day group included somnolence in 14.5% (24/165), dizziness in 9.1% (15/165), oedema peripheral in 5.5% (9/165), and weight gain in 5.5% (9/165).
2. Phase 3 multinational clinical study: In a double-blind controlled study in 763 patients with postherpetic neuralgia, each patient received 14-week treatment with mirogabalin 15 mg (5 mg/day for 1 week, 10 mg/day for 1 week, and then 15 mg/day for 12 weeks: total 14-week treatment), 20 mg (10 mg/day for 1 week and then 20 mg/day for 13 weeks: total 14-week treatment), or 30 mg (10 mg/day for 1 week, 20 mg/day for 1 week, and then 30 mg/day for 12 weeks: total 14-week treatment)^Note) or placebo. The mirogabalin 20- and 30-mg/day groups showed statistically significant improvement in pain scores at Week 14, compared with the placebo group. (See Table 2.)

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The frequencies of adverse reactions were 35.3% (54/153 patients) in the 20-mg/day group and 44.5% (69/155) in the 30-mg/day group. Common adverse reactions in the 20-mg/day group included somnolence in 17.0% (26/153), dizziness in 8.5% (13/153), and weight gain in 4.6% (7/153); those in the 30-mg/day group included somnolence in 22.6% (35/155), dizziness in 14.2% (22/155), and oedema in 7.1% (11/155).
3. Phase 3 multinational clinical studies (long-term studies): In Phase 3, open-label, long-term studies conducted in Asia, which had a 52-week treatment period (a titration period of 4 weeks and a dose-adjustment period of 48 weeks), in 214 patients with diabetic peripheral neuropathic pain or 237 patients with postherpetic neuralgia, the mean pain intensity is shown in the table as follows. (See Table 3.)

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The frequencies of adverse reactions were 27.6% (59/214 patients) in patients with diabetic peripheral neuropathic pain and 39.7% (94/237) in patients with postherpetic neuralgia. Common adverse reactions in patients with diabetic peripheral neuropathic pain included somnolence in 7.9% (17/214), dizziness in 6.1% (13/214), and oedema peripheral in 4.7% (10/214); those in patients with postherpetic neuralgia included somnolence in 13.5% (32/237), dizziness in 10.1% (24/237), and weight gain in 7.2% (17/237).
4. Japanese Phase 3 clinical study: In a Phase 3 open-label study, which had a 14-week treatment period (a titration period of 2 weeks and a fixed-dose period of 12 weeks), in patients with diabetic peripheral neuropathic pain or postherpetic neuralgia and with renal impairment, the pain scores at Week 14 are shown in the table as follows. (See Table 4.)

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The frequencies of adverse reactions were 30.0% (9/30 patients) in patients with moderate renal impairment and 0% (0/5) in patients with severe renal impairment. Common adverse reactions in patients with moderate renal impairment included somnolence in 13.3% (4/30) and dizziness in 6.7% (2/30).
^Note) The approved dose of TARLIGE is 5 mg of mirogabalin twice daily for the initial dose, and 10 mg or 15 mg of mirogabalin twice daily for the effective dose.
Pharmacokinetics: Absorption: Mirogabalin was rapidly absorbed in healthy adults. Following the administration of mirogabalin at a single oral dose of 3, 5, 10, and 30 mg (6 subjects per dose level) in healthy adults, plasma mirogabalin concentrations reached the maximum concentration (Cmax) at 1 h post-dose. Following the administration of mirogabalin at a single oral dose of 15 mg in the fasted and fed states in 30 healthy adults, administration in the fed state resulted in a decrease of Cmax by approximately 18% and a delay of Tmax by 0.5 h, whereas the AUCinf was only reduced by approximately 6%. The effect of food on the absorption rate of mirogabalin was limited, therefore mirogabalin can be given under both fasted and fed condition. Following the administration of mirogabalin at multiple oral doses of 10 mg and 15 mg (6 subjects per dose level) twice daily in Japanese healthy adult subjects for 7 days, steady state was reached by Day 3.
Distribution: Following the administration of mirogabalin at a single oral dose of 3, 5, 10, and 30 mg in 6 healthy adults, the apparent volume of distribution based on the terminal phase (Vz/F) was 78.01 to 87.97 L.
In an in vitro study, mirogabalin labeled with ¹⁴C (abbreviated as ¹⁴C-mirogabalin) was distributed into red blood cells, with a ratio of whole blood concentration to plasma concentration of 0.85 to 0.87 in human. The ¹⁴C-mirogabalin human plasma protein binding ratios, determined by ultracentrifugation, were 23.4% to 25.5% at plasma concentrations of 0.1 to 10 μg/mL.
Biotransformation: Following the administration of ¹⁴C-mirogabalin at a single oral dose of 30 mg (150 μCi) in healthy male adults (6 subjects), approximately 97% of the radioactivity was recovered in the urine, and approximately 76% of the radioactivity in the urine was recovered as unchanged mirogabalin. The metabolite of mirogabalin found in urine, other than the unchanged mirogabalin, was the lactam form of mirogabalin, and accounted for 0.6% of the dose. The N-glucuronide conjugate metabolized by UGT was also found.
Elimination: Following the administration of mirogabalin at a single oral dose of 3, 5, 10, and 30 mg in 6 healthy adults, the apparent total body clearance (CL/F) ranged between 16.50 and 18.24 L/h with a half-life (t_½) of 2.96 to 3.37 h. In these subjects, 63.2% to 71.5% of the dose was excreted, unchanged, in the urine, and renal clearance was 10.4 to 12.4 L/h. Following the administration of ¹⁴C-mirogabalin at a single oral dose of 30 mg (150 μCi) in healthy male adults (6 subjects), a cumulative excretion rate of radioactivity up to 168 h post-dose was ≥ 98%; radioactivity recovered in urine and feces was approximately 97% and 1%, respectively.
Linearity/non-linearity: The Cmax and AUCinf of mirogabalin increased in a dose-proportional manner following the administration of mirogabalin at a single oral dose of 3, 5, 10, and 30 mg and multiple oral doses of 10 mg and 15 mg in healthy adults.
Elderly: Following the administration of mirogabalin at multiple oral doses of 5, 10, and 15 mg (6 subjects per dose level, including 13 subjects younger than 65 years) twice daily in healthy elderly subjects between 55 years and 75 years of age for 14 days, steady state was reached by Day 3, with t_½ of 3.58 to 4.55 h on Day 14. The AUC_0-12h on Day 14 was 1.13 times to 1.24 times of that on Day 1. The pharmacokinetics of mirogabalin in the healthy elderly subjects did not differ significantly from those observed in healthy non-elderly subjects (see Dosage & Administration).
Renal impairment: Following the administration of mirogabalin at a single oral dose of 5 mg in 30 Japanese subjects with normal renal function or renal impairment, AUClast increased in association with decreased creatinine clearance (CLcr). In patients with end-stage renal disease requiring hemodialysis, 15.3% of dosed mirogabalin was removed from blood during 4-hour hemodialysis (see Dosage & Administration). (See Table 5.)

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Hepatic Impairment: Following the administration of mirogabalin at a single oral dose of 15 mg in 16 subjects with mild or moderate hepatic impairment, Cmax in subjects with mild and moderate hepatic impairment was 1.0 and 0.8 times, respectively, higher than that in healthy subjects, and AUCinf in subjects with mild and moderate hepatic impairment was 0.9 and 1.1 times, respectively, greater than that in healthy subjects (see Dosage & Administration).
^Note) The approved dose of TARLIGE is 5 mg of mirogabalin twice daily for the initial dose, and 10 mg or 15 mg of mirogabalin twice daily for the effective dose.
AUCinf: Area under the plasma concentration-time curve up to infinity.
AUClast: Area under the plasma concentration-time curve up to the last quantifiable time.
AUCtau: Area under the plasma concentration-time curve during dosing interval.
Toxicology: Preclinical safety data: In safety pharmacology studies in rats and monkeys, mirogabalin besilate was well-tolerated at clinically relevant doses.
In repeated dose toxicity studies in rats and monkeys, the dose-limiting toxicity of mirogabalin besilate was abnormal clinical signs (i.e. prone position, hypoactivity, staggering gait, ataxia) associated with depression of the central nervous system resulting from exaggerated pharmacological action. The mean AUC_0-24h value at the NOAEL (10 mg/kg/day) in rats, the most sensitive species, was 4.7 times higher than that at the maximum recommended clinical dose of 15 mg twice daily.
Mirogabalin besilate was not teratogenic in rats or rabbits, and did not show reproductive toxicity in males or disturbance in fertility and early embryonic development. But, prolonged proestrus and estrus were observed in the female at the dose of 100 mg/kg/day. In pre- and postnatal development studies including maternal function in rats, prolongation of the pregnancy period was noted at 100 mg/kg/day. In the F1 animals, a low live birth index was noted at 30 mg/kg/day or more. The mean AUC_0-24h value at the NOAEL (10 mg/kg/day) for the next generation was 5.2 times higher than that at the maximum recommended clinical dose of 15 mg twice daily.
Mirogabalin besilate did not show genotoxic potential in the bacterial reverse mutation study, chromosomal aberration study, or single dose rat bone marrow micronucleus study up to at 2000 mg/kg.
Two-year carcinogenicity studies with mirogabalin besilate were conducted in mice and rats. No tumors were observed in mice at exposures up to 13.5 times the mean human exposure at the maximum recommended clinical dose (15 mg twice daily). In rats, an increased incidence of transitional cell papilloma in the urinary bladder was observed only in males at 100 mg/kg/day. However, the incidence of hyperplasia in the urinary bladder did not increase significantly in any group and mirogabalin besilate did not increase the labeling index of Ki-67-positive cells in the urinary bladder up to at 100 mg/kg/day in the 4-, 13-, 26- or 104-week repeated dose studies. At the dose (30 mg/kg/day) which the AUC_0-24h value was 22.1 times higher than the maximum recommended clinical dose (15 mg twice daily), statistically significant increase of incidence of transitional cell papilloma was not observed. Taken together, the tumorigenic potential of mirogabalin besilate was considered to be very low. There is no evidence to suggest an associated risk to humans.
Environmental Risk Assessment (ERA): The environmental risk assessment of mirogabalin besilate has been conducted in accordance to European guidelines on ERA. No environmental impact is anticipated from the clinical use of mirogabalin.

Peripheral neuropathic pain.
TARLIGE is indicated for the treatment of peripheral neuropathic pain in adult.

Posology: For adults, administer mirogabalin at an initial oral dose of 5 mg twice daily, and then increase the dose by 5 mg per dosing with an interval of at least 1 week up to 15 mg twice daily. The dose may be increased or decreased appropriately in the range between 10 mg and 15 mg twice daily, based on individual patient age or symptoms.
Renal Impairment: Since mirogabalin concentrations in plasma may increase in patients with reduced renal function, possibly increasing the risk of adverse reactions, careful administration with close monitoring is necessary for these patients. For patients with renal impairment, the dose and dosing intervals should be adjusted, referring to creatinine clearance levels listed in Table 6. Treatment should be started at a low dose, and the dose should be increased in patients who show confirmed tolerability but insufficient effect (see PHARMACOLOGY: Pharmacodynamics and Pharmacokinetics under Actions). (See Table 6.)

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Pediatric population: Clinical studies in children have not been conducted.
Elderly population: TARLIGE should be administered with care, and dose and dosing interval adjustment based on creatinine clearance levels is required. Elderly patients often have reduced renal function (see PHARMACOLOGY: Pharmacokinetics under Actions).
Elderly patients tend to experience falls resulting in fractures, etc. led by events (e.g., dizziness, somnolence, loss of consciousness) (see Precautions).
Hepatic Impairment: No dose adjustment is required for patients with hepatic impairment (see PHARMACOLOGY: Pharmacokinetics under Actions).
Method of administration: For oral use.
TARLIGE can be taken with or without food (see PHARMACOLOGY: Pharmacokinetics under Actions).

Symptoms: There have been reports on overdoses of up to 60 mg/day in an overseas clinical study in patients with fibromyalgia^Note). Symptoms observed during a mirogabalin overdose included euphoric mood, dysarthria, headache, dysphagia, arthritis, joint swelling, and asthenia.
Treatment: Hemodialysis is reported to remove 15.3% of mirogabalin.
Note) The indication of TARLIGE is peripheral neuropathic pain.

Patients with a history of hypersensitivity to the active substance or to any of the excipients listed in Description.

Dizziness, somnolence, loss of consciousness: Dizziness, somnolence, and loss of consciousness, which may cause falls and subsequent fractures, etc., may occur. Patients being treated with TARLIGE should be monitored closely; if any abnormalities are noted, appropriate measures, such as discontinuation of treatment or dose reduction, should be taken (see Dosage & Administration and Effects on ability to drive and use machines as follows).
Hepatic function disorder: Hepatic function disorder (e.g., AST increased, ALT increased) may occur. Patients being treated with TARLIGE should be monitored closely; if any abnormalities including early symptoms (e.g., general malaise, anorexia) are noted, treatment should be discontinued and appropriate measures should be taken.
Weight gain: Treatment with TARLIGE may cause weight gain. Caution should therefore be exercised for potential occurrence of obesity. If signs of obesity are noted, appropriate measures, such as diet and/or exercise therapy, should be taken. In particular, since weight gain may be associated with dose increase or long-term use, body weight should be measured regularly.
Withdrawal symptoms: Abrupt discontinuation of treatment with TARLIGE may cause drug withdrawal symptoms (e.g., insomnia, nausea, diarrhea, decreased appetite). Treatment with TARLIGE should be discontinued in a careful manner, such as gradual dose reduction.
Ophthalmic disorders: Treatment with TARLIGE may cause ophthalmic disorders (e.g., amblyopia, abnormal vision, vision blurred, and diplopia). Caution should therefore be exercised for potential occurrence of ophthalmic disorders in medical examinations including careful history taking.
Other Precautions: It should be noted that TARLIGE for neuropathic pain is not a causal therapy but a supportive therapy. Therefore, the underlying disease of the pain should be diagnosed and treated concurrently, and the drug should not be used without intention.
In multinational, placebo-controlled studies conducted in Asian countries, suicide-related adverse events were reported in 3 of 1227 subjects (0.24%; completed suicide, 1 subject; suicidal ideation, 2 subjects) in the mirogabalin groups and in 1 of 721 subjects (0.14%; suicidal ideation, 1 subject) in the placebo group.
In multinational, placebo-controlled studies conducted in Asian countries, death cases were reported in 2 of 1227 subjects (0.16%) in the mirogabalin groups and in none of 721 subjects in the placebo group. All of the death cases in the mirogabalin groups occurred in patients with diabetic peripheral neuropathic pain.
Effects on ability to drive and use machines: TARLIGE may cause event(s) (e.g., dizziness, somnolence, loss of consciousness). Patients being treated with TARLIGE must be warned not to operate potentially dangerous machinery, such as driving a car.

Women of childbearing potential/Contraception in males and females: As the potential risk for humans is unknown, effective contraception must be used in women of child bearing potential.
Pregnancy: For pregnant women and women who may be pregnant, TARLIGE should be administered only if the expected therapeutic benefits outweigh the possible risks associated with treatment. An animal study (in rats) has shown that mirogabalin crossed the placenta (see PHARMACOLOGY: Toxicology: Preclinical safety data under Actions).
Breast-feeding: The continuation or discontinuation of breastfeeding should be considered while taking account of the expected therapeutic benefits and the benefits of maternal feeding. An animal study (in rats) has shown that mirogabalin transferred to breast milk (see PHARMACOLOGY: Toxicology: Preclinical safety data under Actions).
Fertility: There are no clinical data on the effects of TARLIGE on female fertility. There was no adverse effect on fertility in an animal study (in rats) (see PHARMACOLOGY: Toxicology: Preclinical safety data under Actions).

Summary of the safety profile: The safety profile of TARLIGE is based on two Phase 3 and one Phase 2 studies (854 patients with diabetic peripheral neuropathic pain and 553 patients with postherpetic neuralgia), and from post-authorisation experience.
The most commonly reported adverse reactions associated with TARLIGE treatment in clinical trials are somnolence (15.4%), dizziness (10.1%) and oedema (6.7%).
Tabulated list of adverse reactions: Adverse reactions from TARLIGE in clinical trials, post-authorisation safety studies and spontaneous reporting are summarized in Table 7.
The following terminologies have been used in order to classify the occurrence of adverse reactions: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). (See Table 7.)

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Mirogabalin is predominantly excreted by renal glomerular filtration and tubular secretion. Major transporters involved in the secretion of mirogabalin are organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, H⁺/organic cation antiporter (MATE) 1, and MATE2-K. Mirogabalin is also metabolized by UDP-glucuronosyltransferases (UGTs). (See Table 8.)

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In vitro study data: Mirogabalin was not metabolized by CYP but was metabolized by UGT1A3, UGT1A4, UGT1A9, UGT2B4, UGT2B7 and UGT2B17.
Mirogabalin was secreted from the kidney and was suggested to be a substrate for OAT1, OAT3, OCT2, MATE1, and MATE2-K.
Mirogabalin did not inhibit or induce major human CYP molecular species, and did not inhibit activities of drug transporters (OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, and MATE2-K). Mirogabalin also did not inhibit activities of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP).
In clinical study data: Co-administration of probenecid (500 mg) with TARLIGE (15 mg) increased the Cmax and AUClast of TARLIGE by 29% and 76%, respectively.
Co-administration of cimetidine (400 mg) with TARLIGE (15 mg) increased the Cmax and AUClast of TARLIGE by 17% and 44%, respectively.
Co-administration of TARLIGE with ethanol or lorazepam had no notable effect on the pharmacokinetics of TARLIGE or these drugs. Co-administration of TARLIGE in with these drugs decreased attention and balance-function more profoundly than monotherapy with TARLIGE.
Co-administration of TARLIGE with tramadol had no notable effect on the pharmacokinetics of TARLIGE or tramadol.

Incompatibilities: Not applicable.
Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product: Precautions Concerning the Dispensing of the Drug: For drugs that are dispensed in a press-through package (PTP), instruct the patient to remove the drugs from the package prior to use. If the PTP sheet itself is mistakenly swallowed, the sharp edges of the sheet may be inserted into and puncture the esophageal mucosa, resulting in serious complications, such as mediastinitis.

Store below 30°C.
Store in the original package in order to protect from moisture.

Drugs for Neuropathic Pain

N02BF03 - mirogabalin ; Belongs to the class of gabapentinoids. Used to relieve pain and other conditions.

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