Remitch

Soft purplish red to dull red film-coated tablet. (See Table 1.)

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Remitch OD tablets 2.5 µg: Each tablet contains 2.5 μg of nalfurafine hydrochloride.
Chemical name: (2E)-N-[(5R, 6R)-17-(Cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-yl]-3-(furan-3-yl)-N-methylprop-2-enamide monohydrochloride.
Molecular formula: C₂₈H₃₂N₂O₅ · HCl.
Molecular weight: 513.03.
Description: Nalfurafine hydrochloride is a white to slightly-yellowish powder. It is very hygroscopic and slightly unstable to light. It is freely soluble in water and methanol, slightly soluble in ethanol (95), and practically insoluble in ethyl acetate and diethyl ether.
Distribution coefficient: 0.95 [1-Octanol/buffer solution of pH 6.8 (LogD)].
Excipients/Inactive Ingredients: D-mannitol, sodium thiosulfate hydrate, crospovidone, magnesium stearate, polyvinyl alcohol (partially hydrolyzed), lactose hydrate, macrogol 400, titanium oxide, red ferric oxide.

ATC Code: V03AX02. Other therapeutic products.
Pharmacology: Pharmacodynamics: Effect on Pruritus: This product inhibited a scratching behavior induced by intradermal administration of histamine in mice, a model wherein the existing antipruritics of antihistamines are effective, and the scratching behavior induced by intradermal administration of substance P in mice, a model wherein antihistamines are resistant. Moreover, a scratching behavior induced by intracisternal administration of morphine in mice, a central itching model wherein antihistamines are ineffective, was also inhibited by this product.
Mechanism of Action: This product has been shown to be a selective κ-opioid receptor agonist based on the results of in vitro receptor binding and agonistic activity study using human opioid receptor expressing cells. (See Table 2.)

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In vitro studies have shown that this product does not bind to the various receptors and ion channels including histamine receptors other than the opioid receptors, and that this product does not inhibit the degranulation response in mast cells. Furthermore, the scratching inhibitory effect of this product in mice induced by intradermal administration of substance P was completely blocked by the intracerebroventricular administration of norbinaltorphimine (nor-BNI) which is an antagonist for κ-opioid receptor.
Dependence: The physical dependence liability of this product is considered to be weak because the withdrawal signs found by the termination of the repeated administration of morphine were barely shown by that of nalfurafine hydrochloride in rats. It is thought that there is no psychological dependence liability on this product because no reinforcing effect was observed on the self-administration study in monkeys.
Clinical studies: Results of nalfurafine hydrochloride (capsule) are shown as follows.
Improvement of pruritus in hemodialysis patients: Confirmatory study: The efficacy once daily repeated-dose oral administration once daily for 14 days was examined using a Visual Analogue Scale (VAS) which is an index of itching in a multicenter, double blind, comparative study in 337 hemodialysis patients who have pruritus refractory to the existing treatment(s). The efficacy, evaluated by the amount of change of VAS from predose to postdose compared to placebo, was confirmed in the 2.5 μg and 5 μg administration groups. (See Tables 3 and 4.)

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Long-term administration study: The efficacy at the time of repeated-dose oral administration of nalfurafine hydrochloride 5 μg once daily for 52 weeks was examined using the VAS in an open-label study in 211 hemodialysis patients who had pruritus refractory to the existing treatment(s). The efficacy of this product, evaluated by the amount of change in VAS from baseline compared to after medication administration, was confirmed. (See Figure 1 and Table 5.)

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No patients showing a psychological or physical dependence on nalfurafine hydrochloride were observed. In addition, tolerance of efficacies was observed in 5 of 211 patients.
Improvement of pruritus in peritoneal dialysis patients: Uncontrolled open-label study: The efficacy of repeated-dose oral administration of nalfurafine hydrochloride (the dosage was 2.5 μg for 2 weeks and continuously increased to 5 μg for 2 weeks) was examined using a VAS, which is an index of itching, in an uncontrolled open-label study in 37 peritoneal dialysis patients who had pruritus refractory to the existing treatment(s). The mean change in VAS from baseline compared to after 2.5 μg administration for two weeks [LOCF: Last Observation Carried Forward] was 24.93 mm [18.67, 31.19] (90% CI), and the lower limit of the 90% CI for the mean change in VAS (18.67 mm) was greater than the threshold value (15.24 mm) which was set before the study.
Improvement of pruritus in patients with chronic liver disease: Confirmatory study: The efficacy of repeated-dose oral administration once daily for 12 weeks was examined using a VAS, which is an index of itching, in a multicenter, double-blind, comparative study in 316 patients with chronic liver disease* who had pruritus refractory to antihistamine agents or antiallergic agents. The primary endpoint was the amount of change in VAS at Week 4 in the administration period (LOCF). The efficacy, evaluated by the amount of change in VAS from predose to postdose compared with placebo, was confirmed in the 2.5 μg and 5 μg administration groups.
*Patients with liver disease in whom the underlying disease has been confirmed, and the hepatic inflammation persists for at least 6 months or progression of disease state of hepatitis is confirmed by diagnostic imaging. (See Tables 6 and 7.)

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Long-term administration study: The efficacy of repeated-dose oral administration of nalfurafine hydrochloride 5 μg once daily for 52 weeks was examined using the VAS in an open-label study in 122 patients with chronic liver disease* who had pruritus refractory to antihistamine agents or antiallergic agents. The efficacy of this product, evaluated by the amount of change in VAS from predose compared with postdose, was confirmed.
*Patients with liver disease in whom the underlying disease has been confirmed, and the hepatic inflammation persists for at least 6 months or progression of disease state of hepatitis is confirmed by diagnostic imaging. (See Figure 2 and Table 8.)

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No patients showing a psychological dependence on nalfurafine hydrochloride were observed. In addition, physical dependence was observed in 1 and tolerance of efficacies was observed in 4 of 122 patients.
Pharmacokinetics: Absorption: Hemodialysis patients (single dose): Changes over time in the plasma concentration and the pharmacokinetic parameters of the unchanged drug after a single-dose oral administration of nalfurafine hydrochloride (capsule) 2.5 or 5 μg to 16 hemodialysis patients are shown as follows. (See Figure 3 and Table 9.)

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Hemodialysis patients (repeated dose): Changes over time in the plasma concentration and the pharmacokinetic parameters of the unchanged drug after repeated-dose oral administrations of nalfurafine hydrochloride (capsule) 2.5 or 5 μg to 14-16 hemodialysis patients are shown as follows. (See Figure 4 and Table 10.)

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At the time of dialysis, t_½ was shortened when compared with that in the absence of dialysis. The t_½ in the presence or absence of hemodialysis is 7.60 ± 2.02 hours and 32.06 ± 15.50 hours, respectively.
Peritoneal dialysis patients (single dose): Changes over time in the plasma concentration and the pharmacokinetic parameters of the unchanged drug after a single-dose oral administration of nalfurafine hydrochloride (capsule) 2.5 or 5 μg to 16 peritoneal dialysis patients are shown as follows. There was no apparent difference in pharmacokinetic parameters of the unchanged drug depending on the types of peritoneal dialysis [Continuous Ambulatory Peritoneal Dialysis (CAPD), Continuous Cycling Peritoneal Dialysis (CCPD)], use/non-use of Automated Peritoneal Dialysis (APD), and the types of dialysate solution. In 1 of 5 patients who received first dialysate exchange at 3 hours post-dose in the 5 μg administration group, there was a tendency of decreasing C_max and AUC_0-∞ of the unchanged drug to 5.37 pg/mL and 156.54 pg·hr/mL, respectively. (See Figure 5 and Table 11.)

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Patients with mild hepatic dysfunction (Child-Pugh grade A): Changes over time in the plasma concentration and pharmacokinetic parameters of the unchanged drug after a single-dose oral administration of nalfurafine hydrochloride (capsule) 2.5 or 5 μg to 12 patients with compensated cirrhosis in Child-Pugh grade A are shown as follows. There was no tendency of increasing C_max and AUC in comparison with healthy adult males. (See Figure 6 and Table 12.)

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Patients with moderate hepatic dysfunction (Child-Pugh grade B): Changes over time in the plasma concentration and pharmacokinetic parameters of the unchanged drug after a single-dose oral administration of nalfurafine hydrochloride (capsule) 2.5 or 5 μg to 30 patients with chronic hepatic disease in Child-Pugh grade B are shown as follows. There was a tendency of increasing C_max and AUC in comparison with patients with mild hepatic dysfunction (Child-Pugh grade A). (See Figure 7 and Table 13.)

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Patients with severe hepatic dysfunction (Child-Pugh grade C): Pharmacokinetics in patients with hepatic dysfunction in Child-Pugh grade C has not been investigated.
Bioequivalence study: Changes over time in the plasma concentration and the pharmacokinetic parameters of the unchanged drug after a single-dose oral administration of nalfurafine hydrochloride (this product and capsule) 5 μg to 30 healthy male adults are shown as follows. The bioequivalence between the existing capsule formulation and this product (with and without water) formulation has been confirmed. (See Figure 8 and Table 14.)

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Distribution: In vitro protein binding rate: The plasma protein binding rate ranged 73.3 to 76.3% in human, and no sex difference was observed.
Animal study: The distribution of high radio activities was observed in the esophagus, liver, and digestive tract and its contents 15 minutes after single-dose oral administration to rat in the whole-body autoradiogram and tissue distribution studies. Radioactivity was observed in the liver, kidneys, thyroid gland, and the contents of the intestines 168 hours after administration.
Metabolism: In vitro microsomal study has shown that the major isoform of metabolizing enzyme was CYP3A4.
Excretion: Pharmacokinetics was examined after a single intravenous administration of the tritiated nalfurafine hydrochloride in 6 healthy adult male volunteers. The excretion rate of feces and urine was 56.0 and 36.2%, respectively, and the accumulated excretion rate was 92.2% within 14 days after administration. Mainly, the unchanged drug was excreted in the urine while the decyclopropylmethyl form of the product was primarily excreted in the feces. The main metabolite was the decyclopropylmethyl form of the product. The glucuronides were also observed.
A removal efficiency of the product by dialysis was evaluated using four kinds of dialysis membrane. The clearance of the unchanged drug was calculated to be 44.6-61.8 mL/min by conversion with a dialysis membrane area of 1.5 m². This is a low level compared to the renal clearance of 170-210 mL/min of the unchanged drug in healthy adult male volunteers. However, the unchanged drug was considered to be removed by dialysis regardless of the types of membrane. In addition, metabolites (decyclopropylmethyl form and glucuronides of the product) were also considered to be removed regardless of the types of membrane.
Toxicology: Preclinical safety data: Single-dose toxicity study: Abnormal respiration (tachypnea and bradypnea), unconsciousness and other symptoms were observed in dead mice and rats in single-dose toxicity studies, but no noteworthy changes were observed at necropsy. In the survival animals, the changes in clinical signs had mainly been observed until 2 days after administration, and then disappeared. In rats, the transient body weight loss occurred and then the weight was increased. At necropsy, no changes associated with drug administration were observed.
Repeated-dose toxicity study: The maximum non-lethal oral dose was 50 mg/kg in rats and was 0.3 mg/kg in dogs, confirming that both were well over the anticipated maximum clinical dose (5 μg/body).
No deaths were observed in any of the repeated-dose toxicity studies. Central changes in clinical signs (such as a decrease in locomotor activity), decreased food consumption, decreased body weight gain, and decrease in prostate and seminal vesicle weights were commonly observed in both rats and dogs. All of these symptoms were reversible, and occurred at lower doses in dogs. The NOAEL was also lower for dogs than for rats.
Genotoxicity study: A bacterial reverse mutation study, a chromosome aberration study in cultured mammalian cells, and a micronucleus study in mice were conducted, and all of the studies were negative, showing that nalfurafine hydrochloride is not genotoxic.
A carcinogenicity study: Long-term carcinogenicity study in mice and rats (24-month repeated oral administration) revealed no any carcinogenicity associated with nalfurafine hydrochloride.
Reproduction toxicity studies: There are studies on embryo-fetal development in rats and rabbits. In rats, delayed estrous cycles, decreased fertility rate, decreased mean number of implantations, decreased implantation rate, decreased numbers of live fetuses were observed. NOAELs for the reproductive ability of parent animals and for embryos/fetuses were both concluded to be 1 mg/kg/day.
In rabbits, a trend toward decreases in fetal body weight and placental weight were observed in rabbits. NOAELs for the reproductive ability of parent animals and for embryos/fetuses were thus concluded to be 0.01 mg/kg/day.
No teratogenicity was observed in either rats or rabbits. In a study on pre- and postnatal development, including maternal function, the NOAELs of nalfurafine hydrochloride for general toxicity, reproduction, and fetus development were all considered to be 0.1 mg/kg/day. Specifically, in the 1 mg/kg/day group, decreased fertility rates caused by abnormal parturition, abortion or total sorption of litters were observed in F₀ dams, and decreased nursing behavior was also observed in postpartum dams.
In F₁ fetuses, low body weight and a tendency toward delayed physical development were observed during the lactation period in the 1 mg/kg/day group. Furthermore, the postnatal survival rate on the 4th day after birth was low, reflecting decreased nursing behavior. Based on these results, administration in pregnant women may adversely affect maternal and child health. (See Use in Pregnancy & Lactation.)
Antigenicity study: In antigenicity studies, the results of several antigenicity studies were all negative. Nalfurafine hydrochloride was considered to have no antigenicity.
Dependence: Although the structure of nalfurafine hydrochloride includes a morphinan skeleton, the results in rats and monkeys suggested that the physical dependence associated with nalfurafine hydrochloride was very weak compare with that associated with morphine, and that nalfurafine hydrochloride is not associated with psychological dependence. A long-term study in patients with chronic liver disease and hemodialysis patients revealed no dependence.
Phototoxicity study: In vitro and in vivo phototoxicity studies were also conducted because the maximum absorption of nalfurafine hydrochloride is at around 280 nm. The results suggested that phototoxicity is unlikely to develop at the anticipated clinical dose (2.5 to 5 μg/body).

Treatment of cutaneous pruritus in hemodialysis patients (use only when sufficient efficacy is not obtained with the existing therapies or treatments).

The recommended dose for adults is 2.5 μg of nalfurafine hydrochloride once daily, administered orally after an evening meal or before bedtime. The dose can be increased in accordance with the symptoms, the maximum dose is 5 μg once daily.
Precautions: A sufficient amount of time should be provided from administration of this product to the beginning of hemodialysis. The blood concentration of this product may decrease when the time of administration of this product to hemodialysis is short, because this product is eliminated by hemodialysis. (See Influence of Hemodialysis under Interactions.)
Although this product disintegrates in the oral cavity, this product should be swallowed with saliva or water, since the drug is not absorbed from the mucosa of the oral cavity. (See Precautions concerning use under Precautions.)
Adjusting the timing of the medication must be under discretion and monitoring of the physician only.

Signs, Symptoms: Overdosing on this product may induce symptoms such as hallucination, anxiety, severe sleepiness, and insomnia.
Treatments: Discontinue administration of this product and perform appropriate symptomatic therapies if needed. It is confirmed that this product is eliminated by hemodialysis. (See Influence of Hemodialysis under Interactions.)

Patients with a medical history of hypersensitivity to any of ingredients contained in this product.

Careful administration (Caution should be exercised when administering REMITCH to the following patients): Elderly patients.
Patients with hepatic dysfunction: No clinical studies have been conducted in patients with severe hepatic dysfunction (Child-Pugh grade C); Blood concentration may increase for patients with moderate hepatic dysfunction (Child-Pugh grade B).
Patients with renal impairment: Blood concentration may increase.
Important precautions: For the use of this product in patients with severe hepatic dysfunction (Child-Pugh grade C), risk/benefit should be considered, and the patient's condition should be carefully monitored during the treatment period.
If no efficacy is observed after using this product, be careful not to aimlessly prescribe it to patients over a long period of time.
Endocrine dysfunction, such as an elevation of the prolactin level, may appear when receiving this product. Therefore, it is desirable to examine the patient as needed.
Precautions concerning use: Precautions regarding dispensing: If the product comes in a press-through package (PTP), instruct the patients to remove the product from the PTP sheet before use. It has been reported that, if the PTP sheet is swallowed, its sharp corners may penetrate the esophageal mucosa, leading to perforation and severe complications such as mediastinitis.
Precautions related to storage: Store unopened packages as aluminum pillow packages (with oxygen absorbers). If the packages are open, store this product away from moisture and take it as soon as possible.
Precautions related to administration: This product can be swallowed with saliva after placing it on the tongue, wetting it, mashing it slightly with the tongue, and then letting it disintegrate. This product can also be taken by swallowing with a drink of water.
Other precautions: An animal study in dogs has shown that intravenous administration of this product at 0.1 μg/kg or more decreased blood pressure under general anesthesia.
An animal study in rats has shown that intramuscular administration of this product at 40 μg/kg/day or more has shown a decrease in the conception rate.
Effects on ability to drive and use machine: Since this product may induce sleepiness, dizziness, etc., patients should be cautioned against engaging in potentially hazardous activities requiring alertness, such as operating machinery or driving a car.
Use in the Elderly: In general, elderly patients often have reduced physiological functions. Thus, this product should be administered with care to elderly patients while monitoring the patients' conditions.
Use in Children: The safety of this product in premature, neonates, nursing infants, infants and children has not been established (no clinical studies have been conducted in pediatric patients).

It is not recommended to use this product in female patients who are pregnant or who may possibly be pregnant. An animal study (in rats) has shown that the product is transferred to the placenta, and induces a reduction of the number of viable fetuses, a decline in the birthrate, and weight reduction in newborn pups.
For breast-feeding women, continuation or discontinuation of breastfeeding should be considered based on the therapeutic benefits and the benefits of breastfeeding. An animal study (in rats) has shown that the product is excreted in breast milk.

Improvement of pruritus in hemodialysis patients: Confirmatory study, adverse reactions were reported in 25.0% of patients (28/112) in the 2.5 μg group and 35.1% of patients (40/114) in the 5 μg group. The major adverse reactions in the 2.5 μg group were insomnia in 7.1% of patients (8/112), sleepiness in 4.5% (5/112), constipation and prolactin increased each in 2.7% (3/112); the major adverse reactions in the 5 μg group were insomnia in 14.0% (16/114), constipation in 7.0% (8/114), sleepiness in 3.5% (4/114), itching aggravated, prolactin increased, and thyroid stimulating hormone increased each in 2.6% (3/114). Long-term administration study, adverse reactions were reported in 48.8% of patients (103/211). The major adverse reactions were insomnia in 20.4% of patients (43/211), constipation in 7.1% (15/211), prolactin increased in 3.3% (7/211), and sleepiness in 2.4% (5/211).
Clinically significant adverse reactions: Hepatic function disorder, Jaundice (both incidence unknown): Hepatic function disorder accompanied by markedly increased AST, ALT, Al-P and γ-GTP, and jaundice may occur. (See Table 15.)

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This product is mainly metabolized by hepatic metabolizing enzyme CYP3A4: Precautions for coadministration, nalfurafine hydrochloride should be administered with care when coadministered with the following drugs. (See Table 16.)

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Coadministration with ketoconazole (oral formulation): Nalfurafine hydrochloride was administered to 22 healthy adult male volunteers at a single oral dose of 10 μg alone or co-administrated with repeated-dose of ketoconazole. The AUC_0-∞ of this product became 160.5% by co-administrating ketoconazole. Thus, ketoconazole affected the pharmacokinetics of nalfurafine hydrochloride.
Note: The recommended dose of this product is 2.5 μg.
In vitro study, metabolism: The influence on the AUC of nalfurafine hydrochloride was investigated using in vitro metabolism evaluation system. It was shown that the AUC can possibly become a maximum of 5.5, 2.5 and 2.3 times in co-administration with ketoconazole, midecamycin, and cyclosporin, respectively.
In vitro study, P-glycoprotein: An in vitro study with human P-glycoprotein (MDR1) expressing LLC-PK1 cells, has shown that nalfurafine hydrochloride is found to be a substrate for P-glycoprotein, but it does not affect the transport of digoxin via P-glycoprotein. In the other in vitro study with the same cells, the P-glycoprotein-mediated transport of nalfurafine hydrochloride is inhibited by ketoconazole, verapamil hydrochloride, cyclosporine, tacrolimus and cetirizine hydrochloride.
In vitro study, non-absorbable agents: In the result of the in vitro adsorption test with non-absorbable agents, the adsorption rate of nalfurafine hydrochloride with sevelamer hydrochloride (anion exchange resin agent), a drug to treat hyperphosphatemia, was 11.9%-14.7%, and the adsorption rates of the product with sodium polystyrene sulfonate (cation exchange resin agent) and calcium polystyrene sulfonate (cation exchange resin agent), drugs to treat hyperkalemia, were 62.4%-72.7% and 98.8%-98.9%, respectively.
Influence of Hemodialysis: The effect of frequency of dialysis (1, 2 or 3 times a week), dialysis time (2, 4 or 6 hours), treatment time of dialysis (morning, afternoon or night) and interval from medication to dialysis (4, 8 or 12 hours) on the plasma concentration of nalfurafine hydrochloride (capsule) from the time of medication was evaluated by a simulation method.
The results showed the plasma concentration may decline if the hemodialysis was conducted within 4 hours following medication administration. However, such a possibility was ruled out if the hemodialysis occurred 8 hours or more after drug administration. It was thought that the other factors do not influence the plasma concentration.

Incompatibilities: Not applicable.

Do not store above 30°C.
Store in a tight container.

Other Therapeutic Products

V03AX02 - nalfurafine ; Belongs to the class of other therapeutic products. Used in the management of pruritus in haemodialysis patients.

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