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Kyorin Pharmaceutical Co., Ltd. Revised: September 2016 (28th version) 1 Standard Commodity Classification No. of Japan 87449 - LEUKOTRIENE RECEPTOR ANTAGONIST - ANTI-BRONCHIAL ASTHMA AND ALLERGIC RHINITIS DRUG ® KIPRES Tablets 5mg KIPRES® Tablets 10mg < The Japanese Pharmacopoeia Montelukast Sodium tablets > ® KIPRES OD Tablets 10mg < Montelukast sodium orally disintegrating tablets > Storage Film coated tablets 5mg/10mg: Store at Approval No. room temperature, protect from light . Date of listing in the OD tablets 10mg: Store at room NHI reimbursement temperature price Date of initial Expiration date marketing in Japan Indicated on package Date of latest (Use up the film cotaed tablets as soon reexamination as possible after opening the seal, even Date of latest approval if it is before expiration date.) of indicaion Film coated tablets 5mg Film coated tablets 10mg OD tablets 10mg 22000AMX00010000 22000AMX0040000 22700AMX00773000 April 2008 June 2008 December 2015 April 2008 August 2001 December 2015 March 2016 - January 2008 - International birth date July 1997 - July 1997 Cautions See “PRECAUTIONS FOR HANDLING”. CONTRAINDICATIONS (This product is contraindicated in the following patients.) Patients who are hypersensitive to any component of KIPRES Product description Active ingredient Inactive ingredient Dosage form Color Appearance Diameter Weight Identification code Brand name DESCRIPTION Brand name Thickness Active ingredient KIPRES KIPRES Tablets5mg Tablets10mg Montelukast 10 mg Montelukast 5 mg : The Japanese : The Japanese Pharmacopoeia (JP) Pharmacopoeia (JP) Lactose monohydrate, crystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, red ferric oxide, yellow ferric oxide, carnauba wax Film-coated tablets Beige Long diameter:7.6 mm Short diameter:5.6 mm 8.0 mm Inactive ingredient Dosage form Color 2.9mm About 103mg KP-374 KIPRES OD Tablets10mg Montelukast 10 mg : The Japanese Pharmacopoeia (JP) D-mannitol, gelatin, sucralose, flavor Orally disintegrating tablet White Diameter Appearance About 9.2mm Thickness Weight Identification code About 6.2mm About 34mg KP-375 (package) 4.1mm About 205mg KP-372 2 Kyorin Pharmaceutical Co., Ltd. INDICATIONS Bronchial asthma, Allergic rhinitis DOSAGE AND ADMINISTRATION < Bronchial asthma> The usual dosage for adults is 10 mg as montelukast orally administered once daily at bedtime. < Allergic rhinitis> The usual dosage for adults is 5 - 10 mg as montelukast orally administered once daily at bedtime. PRECAUTIONS FOR DOSAGE AND ADMINISTRATION KIPRES Tablets5mg, KIPRES Tablets10mg Since the montelukast film-coated tablet is not biologically equivalent to the montelukast chewable tablet, and since the bioavailability of the montelukast chewable tablet is higher compared to the montelukast film-coated tablet 1), the montelukast film-coated 5-mg tablet and the montelukast chewable 5-mg tablet should not be substituted with each other. KIPRES Tablets5mg, KIPRES Tablets10mg, KIPRES OD Tablets10mg For adult patients with concomitant bronchial asthma and allergic rhinitis in whom montelukast should be used to treat bronchial asthma, 10 mg of montelukast should be given orally once daily at bedtime. PRECAUTIONS 1. Important Precautions 1) Patients with asthma should be advised to continue taking KIPRES not only during periods of worsening asthma, but also while their asthma is controlled. 2) Because KIPRES differs from bronchial dilators, steroids, etc., it is not a drug to relieve existing asthma attacks. This fact must be fully explained to the patients. 3) If a major attack is observed when administering KIPRES to a bronchial asthma patient, a bronchial dilator or steroid must be administered. 4) If the patient is receiving long-term steroid treatment and the plan is to reduce the amount of steroids by administering KIPRES, this should be accomplished gradually under strict supervision. 5) If the patient has been able to reduce the amount of steroid support by administering KIPRES, be cautious about the possibility of reoccurrence of the original symptoms. 6) Psychiatric symptoms including depression, suicidal ideation, suicide and aggressive behavior have been reported although a causal relationship with this drug is not clear. Therefore, the patient's condition should be sufficiently observed. (See the "Other Precautions" subsection) 7) There are reports that Churg-Strauss syndrome-like angiitis have occurred during use of leukotriene antagonists, which includes KIPRES. These symptoms are mainly produced when reducing or suspending the use of oral steroids. When using KIPRES, be cautious about eosinophil count and angiitic symptoms (numbness, weakness of limbs, pyrexia, arthralgia, and infiltration of the lung, etc.) 8) When the efficacy of KIPRES is not observed, therapy with KIPRES should not be continued randomly for a long-term period. 2. Drug Interactions This drug is mainly metabolized by the drug metabolizing enzymes cytochromes P450 (CYP) 2C8/2C9 and 3A4. [See the “PHARMACOKINETICS” section.] [Careful coadministration (This drug should be coadministered with caution.)] Drug Phenobarbital Signs, symptoms and treatment The action of Mechanism factors and this drug may be CYP3A4, thereby reduced. promoting the risk Phenobarbital induces metabolism of this drug.[See the "PHARMACOKINET ICS" section.] 3. Adverse Reactions <Bronchial asthma> In clinical studies conducted in Japan, 66 adverse reactions were reported in 46 (8.8%) of 523 patients. The most frequently reported adverse reactions observed were diarrhea (9 events, 1.7%), abdominal pain (7 events, 1.3%), nausea (6 events, 1.1%), heart burn (5 events, 1.0%) and headache (5 events, 1.0%). Also, 80 abnormalities in laboratory test findings were observed in 49 patients of 507 patients and the most frequently reported abnormalities were increased ALT (GPT) (14 events in 505 patients), increased γ-GTP (9 events in 463 patients) and increased alkaline phosphatase (8 events in 476 patients). (date at the time of approval) In the special drug-use- surveillanceconducted in Japan, 116 cases (including abnormal laboratory test values) of adverse reactions were observed in 94 patients out of 3,891 patients evaluated for safety (2.4%). The main adverse reactions were hepatic function abnormal, increased blood lactate dehydrogenase, increased blood alkaline phosphatase,rash in 8 cases each respectively (0.2%), and pruritus in 6 cases (0.2%).[At the end of reexamination] < Allergic rhinitis > In clinical studies conducted in Japan, 88 adverse reactions were reported in 70 (4.2%) of 1678 patients. The most frequently reported adverse reactions observed were dry mouth (14 events, 0.8%), somnolence (13 events, 0.8%), epigastric discomfort (9 events, 0.5%), headache (5 events, 0.3%), diarrhea (5 events, 0.3%) and malaise (5 events, 0.3%). No adverse reaction more than 1% was reported. Also, 51 abnormalities in laboratory test findings were observed in 46 patients of 1672. The most frequently reported abnormalities were increased ALT (GPT) (9 Kyorin Pharmaceutical Co., Ltd. events in 1672 patients), white blood cell count increased (6 events in 1670 patients) and occult hematuria (6 events in 1671 patients) and similar to the ones observed in bronchial asthma patients. (date at the time of approval) In the post-marketing survey(drug use surveillance and special drug use surveillance) conducted in Japan, 9 cases (including abnormal laboratory test values) of adverse reactions were observed in 9 patients out of 1,365 patients evaluated for safety (0.7%). The main adverse reactions were somnolence in 2 cases (0.1%), pruritus generalized in 2 cases (0.1%). [At the end of reexamination] 1) Clinically significant adverse reactions (1) Anaphylaxis (frequency unknown) Since anaphylaxis may occur, close observation should be maintained. If symptoms appear, this drug should be discontinued immediately and appropriate measures should be taken. (2) Angioedema (frequency unknown) Since angioedema may occur, close observation should be maintained. If symptoms appear, this drug should be discontinued immediately and appropriate measures should be taken. (3) Fulminant hepatitis(frequency unknown), hepatitis(frequency unknown), hepatic dysfunction(0.01%), jaundice (frequency unknown) Since fulminant hepatitis, hepatitis, hepatic dysfunction and jaundice may occur, close observation should be maintained. If abnormalities are observed, this drug should be discontinued and appropriate measures should be taken. (4) Toxic epidermal necrolysis (TEN) (frequency unknown), oculomucocutaneous syndrome (Stevens-Johnson syndrome) (frequency unknown), erythema multiforme (0.01%) Since toxic epidermal necrolysis, oculomucocutaneous syndrome and erythema multiforme may occur, close observation should be maintained. If abnormalities are observed, this drug should be discontinued and appropriate measures should be taken. (5)Thrombocytopenia(frequency unknown) Thrombocytopenia (initial symptoms: bleeding tendency such as purpura, nose bleeding and gingival bleeding) may occur. Therefore, if such a symptom as this occurs, this drug should be discontinued and appropriate measures should be taken. 2) Other Adverse Reactions If the following symptoms or abnormalities appear, appropriate measures such as discontinuation of therapy should be considered. 0.1% <1% Hyper- Rash, sensitivity pruritus <0.1% Urticaria Incidence unknown 3 Psychiatric Headache, Restlessness, Dream and nervous somnolence insomnia, abnormalities, hallucination, irritability, dizziness, seizure, sensory agitation, abnormality tremor, (numbness) somnambu- system lism, disorientation, mental concentration decreased, memory impairment, delirium Respiratory Pulmonary eosinophilia Gastro- Diarrhea, Heartburn, intestinal abdominal vomiting, system pain, constipation, epigastric stomatitis discomfort, nausea Hepatic Hepatic function abnormal, increased AST (GOT), increased ALT (GPT), increased alkaline phosphatase , increased γ-GTP, increased total bilirubin Musculoske Myalgia letal system including muscle cramps, arthralgia Others Dry mouth, Hematuria, bruise, occult sugar urinary, weakness, hematuria edema, fatigue, malaise, white enuresis blood cell count increased, protein urine, blood Hepatic triglycerides eosinophilic increased, infiltration Dyspepsia 4 Kyorin Pharmaceutical Co., Ltd. bleeding,tend ency (nose bleeding, purpura), palpitation, urinary frequency, pyrexia, alopecia The adverse reaction frequency was calculated based on clinical studies, post-marketing surveys (drug-use-results survey, specific drug-use-results survey, and post marketing clinical studies) of Tablets, Chewable Tablets and Fine Granules conducted in Japan. 4. Use during Pregnancy, Delivery or Lactation 1) KIPRES should be administered to pregnant women or women suspected of being pregnant only when it is judged that the benefits from the treatment exceed the possible risks. [The safety of KIPRES in pregnant women has not been established. During worldwide marketing experience, congenital limb malformations have been reported in the offspring of women being treated with KIPRES during pregnancy. Most of these women were also taking other asthma medications during their pregnancy. A causal relationship between these events and KIPRES has not been established.] 2) Caution should be used in the administration of KIPRES to nursing mothers. [In animal studies (rats), it has been reported that KIPRES is secreted into breast milk.] 5. Pediatric Use <Bronchial asthma> 1) For pediatric patients ≥6 years of age, montelukst chewable tablet 5-mg should be administered once daily at bedtime. 2) For pediatrics ≥1 year and <6 years of age, montelukast fine granules 4-mg should be administered once daily at bedtime. 3) The safety of montelukast formulations in babies under 1 year of age, newborns and premature babies has not been fully established. [Due to lack of domestic experience with montelukast formulations] <Allergic rhinitis> The safety of montelukast formulations in children has not been established. [Due to lack of domestic experience with montelukast formulations] 6. Precautions concerning Use 1) KIPRES Tablets5mg, KIPRES Tablets10mg At the time of delivery:When drugs packed in a PTP sheet are used, patients should be instructed to take the drugs out of the sheet. [It has been reported that when patients mis-swallowed drugs with a PTP sheet (after failing to take the drugs out of the sheet), a hard, sharply angled edge of the sheet struck to the esophageal mucosa. Furthermore, if perforation occurred, serious complications, such as mediastinitis were reported.] 2) KIPRES OD Tablets10mg (1) At the time of delivery: The following instructions should be provided: ①The drug must be removed from the blister sheet before ingestion. [If the blister packaging is swallowed, the sharp corners of the packaging may puncture the esophageal mucosa, resulting in severe complications such as mediastinitis.] ②To remove the drug from the blister sheet, peel off the sheet from the back of the foil completely and take the drug out carefully. Do not push a OD tablet though the foil without first peeling off the sheet because breakage may occur since OD tablets are characteristically soft compared to regular tablets. If chipping or breakage occurs, all pieces of the OD tablets should be ingested. ③The drug should only be removed from the blister sheet immediately before use since this drug absorbs moisture. (2) At time of administration: Since KIPRES OD tablets will disperse after placement on the tongue, it can be swallowed without or with water. 3) KIPRES Tablets5mg, KIPRES Tablets10mg, KIPRES OD Tablets10mg KIPRES may be taken with or without food. 7. Other Precautions The result of a pooled analysis of 41 placebo-controlled clinical studies indicated that while suicidal ideation was observed in one out of 9,929 patients in the montelukast group, no suicidal ideation was observed in 7,780 patients in the placebo group.2) Also, the result of a separate pooled analysis of 46 placebocontrolled clinical studies indicated that behavior-related adverse experiences (including insomnia and irritability) were observed in 319 (2.73%) out of 11,673 patients in the montelukast group and 200 (2.27%) out of 8,827 patients in the placebo group. No statistically significant difference was observed between them.3) PHARMACOKINETICS 1. Blood Concentration 1) Results of Domestic Clinical Studies (1) Following a single oral dose of montelukast filmcoated tablets 10-mg to 8 healthy adults in the fasted state, the peak plasma concentration (Cmax, 526 ng/mL) of montelukast was reached in 3.9 hours (Tmax), and plasma concentrations declined with an apparent half-life (t1/2) of 4.6 hours (Figure 1). Cmax and the area under the plasma concentration-time curve (AUC0→∞ ) increased proportionally with dose in the range of 2 to 50 mg (Table 1). 4) Kyorin Pharmaceutical Co., Ltd. 5 (fasted condition) Fig.1 Plasma Concentration Profile Following Single Oral Administration of Montelukast Film-coated Tablets 10mg in Healthy Adults (ng/mL) 1000 10mg 10 mg n=8:平均値±標準偏 差n=8, Mean±S.D. Plasma concentration ◆ 血 漿 中 濃 100 度 Table 2 Pharmacokinetic Parameters in Healthy Adults (fasted condition) With water (hr) 10 Table 01 Pharmacokinetic in16Healthy 20Adults 4 8 Parameters 12 時間 Dose (mg) Tmax (hr) 2 2.8±0.9 108±23.1 10 3.9±1.5 50 3.6±1.2 Cmax Time t1/2 (ng/mL) (hr) 24 AUC0→∞ (ng·hr/mL) 4.34±0.76 753±242 526±138 4.57±0.39 3840±906 2550± 4.63±0.41 19100± 1250 7910 (2) Administration of montelukast film-coated tablets 10mg after meal to 8 healthy adults resulted in a 24% increase in AUC0→∞ from 3,420 ± 598 ng · hr/mL to 4,240 ± 1,120 ng · hr/mL compared with administration in the fasted state. No differences in Tmax (fasting: 4.0 ± 1.1 hr, after meal: 4.4 ± 1.8 hr) and t1/2 (fasting: 4.31 ± 0.58 hr, after meal: 4.30 ± 0.35 hr) were observed when administered after meal and in the fasted state. 4) (3) When montelukast film-coated tablets 10-mg was orally given once daily to 8 healthy adults at a 10-mg dose for 7 consecutive days, the Cmax was 580 ± 136 ng/mL on the 1st day and 660 ± 124 ng/mL on the 7th day. No clinically important accumulation of KIPRES was observed due to multiple administration, as the AUC 0-24 hr on 7th day agrees well with the AUC0→∞ on 1st day. 4) (4) Following the administration of a single oral dose of montelukast OD tablets 10 mg (1 tablet without or with water) or montelukast film-coated tablet 10 mg 1 tablet with water in healthy adult males (120 subjects) in a fasted state in a crossover trial, pharmacokinetic parameters and change in plasma concentrations of montelukast were as shown below. The results demonstrate bioequivalence of montelukast OD 10 mg (without and with water) relative to montelukast film-coated tablet 10 mg since the 90% confidence intervals of the geometric mean ratios for Cmax and AUC0-t were within log (0.8) and log (1.25).5) Fig.2 Plasma Concentration Profile Following Single Oral Administration of Montelukast OD tablets 10mg and Montelukast Film-coated Tablets 10mg in Healthy Adults OD tablet 10mg Mean±S.D. No Yes N 12 0 11 9 Film-coated 11 tablets 10mg Yes 9 Mean±S.D. OD tablet 10 mg (without water) / Film-coated tablet 10 mg Geometric mean ratio (90% CI) OD tablet 10 mg (with water) / Film-coated tablet 10 mg Geometric mean ratio (90% CI) Cmax (ng/mL) 588± 129 531± 138 AUC0-t (ng/hr/mL) 3917± 1001 3638± 1036 Tmax (hr) 2.4± 1.1 2.1± 0.9 t1/2 (hr) 4.6± 2.4 4.2± 0.5 495± 105 3517± 878 3.6± 1.4 4.2± 0.6 1.17 (1.10 to 1.24) 1.10 (1.05 to 1.15) - - 1.06 (1.01 to 1.11) 1.03 (0.99 to 1.07) - - 2) Results of Clinical Studies Conducted Overseas (Reference) (1) Following a single oral dose of montelukast filmcoated tablets 10-mg to the healthy elderly (65 to 73 years of age), the Cmax (495 ng/mL) was achieved in 2.8 hours, and plasma concentrations declined with a t1/2 of 6.6 hours. AUC0→∞ in the elderly (3,423.2 ± 1,344.7 ng · hr/mL) was not significantly different from that in the healthy non-elderly (3,624.0 ± 1,257.8 ng · hr/mL, 20 to 48 years of age). 6) (2) Following a single oral dose of montelukast filmcoated tablets 10-mg to patients with mild-tomoderate hepatic insufficiency and clinical evidence of cirrhosis, the Cmax (313 ng/mL) was achieved in 4.0 hours, and plasma concentrations declined with a t1/2 of 8.6 hours. The t1/2 of the patients was slightly longer compared with 4.7 hours in healthy adults, and the AUC0→∞ increased by 41% from 2,248.7 ± 812.1 ng · hr/mL to 3,167.2 ± 1,300.5 ng · hr/mL. 7) (3) Bioavailability of KIPRES in healthy adults was 58% to 67%.8) 2. Distribution The binding of montelukast with human plasma proteins was 99.6%. Montelukast was more than 99% bound to both albumin and α1-acid glycoproteins at physiological concentrations. 9) 6 Kyorin Pharmaceutical Co., Ltd. 3. Metabolism The main metabolites of montelukast in human are side chain methyl hydroxylated metabolites and benzylic methylene hydroxylated metabolites. Cytochromes P450 (CYP) molecular species CYP2C8/2C9 and 3A4 are involved in the formation of these metabolites, and CYP2C8 is the main enzyme in the metabolism of montelukast. It has been confirmed that side chain methyl hydroxylated metabolites are further metabolized oxidatively to carboxylic acid metabolites. Based on further in vitro results, therapeutic plasma concentrations of montelukast do not inhibit CYP3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. 10) ~13) Also, other in vitro studies have shown that montelukast is an inhibitor of CYP2C8. However, data from an overseas clinical drug-drug interaction study involving montelukast and a representative drug primarily metabolized by CYP2C8 (rosiglitazone) demonstrated that montelukast does not inhibit CYP2C8 in vivo. 14) Therefore montelukast is not anticipated to alter the metabolism of drugs metabolized by this enzyme (e.g. paclitaxel.) 4. Excretion 1) Results of Domestic Clinical Studies Following single 400-mg oral administration of montelukast capsules to healthy adults, unchanged drug was not detected in the urine. 4) 2) Results of Clinical Studies Conducted Overseas (Reference) During the 5 days after single oral administration of 102 mg of radiolabeled montelukast capsules to healthy adults, 86 % of the radioactivity was recovered in feces and 0.1 % in urine. 15) 5. Coadministration with other agents (Results of Clinical Studies Conducted Overseas, Reference) 1) Phenobarbital 16) When 100 mg phenobarbital (repeated administration for 14 days) was administered to healthy adults and then montelukast film-coated tablets 10 mg (single administration) was orally coadministered, the AUC0-∞ of montelukast was reduced by approximately 40%. 2) Theophylline 17) When a high oral dose of montelukast capsules (200 mg qd repeated administration for 6 weeks or 200 mg tid repeated administration for 8 days) was coadministered with an oral dose of theophylline (250 mg single administration) to healthy adults or coadministered with an intravenous dose of theophylline (5 mg/kg single administration), a decrease in plasma concentrations of theophylline was observed. Theophylline plasma concentrations did not change when an oral 10-mg dose of montelukast film-coated tablets (repeated administration for 10 days) was coadministered with an intravenous dose of 5 mg/kg theophylline (single administration). 3) Prednisone, Prednisolone Following oral coadministration of 200 mg montelukast capsules (repeated administration for 6 weeks) with 20 mg prednisone (single administration) to healthy adults, the AUC0-∞ of prednisone was significantly lowered compared with placebo group. However, the AUC0-∞ of prednisone was not changed between before and after the administration of 200 mg montelukast capsules within the same subjects. The pharmacokinetics of the active metabolite prednisolone was not changed. Coadministration of 200 mg montelukast capsules (repeated administration for 6 weeks) with 20 mg intravenous prednisolone (single administration) to healthy adults had no effect on the pharmacokinetics of either prednisone or prednisolone. 4) Oral contraceptives 18) (ethinyl estradiol/norethindrone 35 μg/1 mg) Following oral coadministration of 100 mg montelukast capsules (repeated administration for 8 days) with oral contraceptives (ethinyl estradiol/norethindrone 35 μg/1 mg single administration) to healthy adults, the pharmacokinetics of either ethinyl estradiol or norethindrone was not affected. 5) Digoxin 19) Following oral coadministration of montelukast filmcoated tablets 10 mg (repeated administration for 7 days) with 0.5 mg digoxin (single administration) to healthy adults, the pharmacokinetics of immunoreactive digoxin was not affected. 6) Warfarin 20) Following oral coadministration of montelukast filmcoated tablets 10 mg (repeated administration for 7 days) with 30 mg warfarin (single administration) to healthy adults, the plasma total drug concentrations of warfarin were not affected. Also, no effect on prothrombin time of warfarin was observed. (Note) The approved dosage of KIPRES for adult bronchial asthma is 10 mg. The approved dosage of KIPRES for adult allergic rhinitis is 5 - 10 mg. CLINICAL STUDIES In clinical studies conducted in Japan, the tolerability of KIPRES has been shown to be up to 400 mg/day in healthy adults. 4) <Bronchial asthma> 1. In clinical studies including a double-blind comparative study conducted in Japan, the efficacy rate of KIPRES 10 mg group was 55.6% (145/261 patients) for definitive general improvement in adult patients with bronchial asthma. Also, the efficacy was 56.1% (32/57 patients) in patients 65 years of age and older and was similar to that for patients less than 65 years of age (113/204 patients, 55.4%). Furthermore, the incidence of adverse reactions in patients 65 years of age and older was 9.0 % (10/111 patients) and Kyorin Pharmaceutical Co., Ltd. was similar to the incidence of 8.7% in patients less than 65 years of age (36/412 patients). 2. In double-blind, comparative Phase III clinical studies in patients with bronchial asthma, the efficacy rate for KIPRES 10 mg group in final general improvement is 58.5% (83/142 patients) and that for pranlukast hydrate (450 mg) is 46.0% (63/137 patients). The non-inferiority (non-inferiority margin Δ=10%) of KIPRES to pranlukast were demonstrated. 21) <Allergic rhinitis> 1. In a phase II dose-finding study in approximately 900 patients with seasonal allergic rhinitis, the change from baseline (LS mean) of composite nasal symptoms score [average of daytime nasal symptoms score* and nighttime nasal symptoms score** (average over the 2-week treatment period)] are -0.47 in montelukast film-coated tablets 5 mg group and -0.47 in montelukast film-coated tablets 10 mg group. Both group showed significant improvement of composite nasal symptoms score compared with placebo (0.37). 22) 2. In a phase III double blind study in approximately 1400 patients with seasonal allergic rhinitis, the change from baseline (LS mean) of composite nasal symptoms score [average of daytime nasal symptoms score* and nighttime nasal symptoms score** (average over the 2-week treatment period)] are -0.19 in montelukast film-coated tablets 5 mg group, -0.19 in montelukast film-coated tablets 10 mg group, and -0.20 in pranlukast hydrate 450 mg group. The noninferiority (non-inferiority margin Δ=0.085) of KIPRES to pranlukast hydrate were demonstrated. 23) *: Compilation of the symptoms score of nasal congestion, rhinorrhea, and sneezing **: Compilation of the symptoms score of nasal congestion, difficulty going to sleep, and nighttime awakening (Note) The approved dosage of KIPRES for adult bronchial asthma is 10 mg. The approved dosage of KIPRES for adult allergic rhinitis is 5 - 10 mg. PHARMACOLOGY Mechanism of Action <Bronchial asthma> Montelukast binds with high selectivity to type 1 cysteinyl leukotriene (CysLT1) receptors, thereby inhibiting the pathophysiologic actions (bronchoconstriction, vascular permeability, and mucus secretion) of the pro-inflammatory mediators LTD4 and LTE4. Due to this mechanism of action, montelukast significantly improves parameters of asthmatic inflammation contributing to its anti-asthmatic effect. <Allergic rhinitis> In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both early- and latephase reactions and are associated with symptoms of allergic rhinitis. Intranasal challenge with CysLTs has been shown to increase nasal airway resistance and symptoms of nasal obstruction. Montelukast blocks the actions of leukotriene 7 receptors, which suggestively play an important role in relief of the symptoms of allergic rhinitis. 1. LT Receptor Antagonism (Receptor Binding Studies) In receptor binding studies using membranes isolated from guinea pig lung, U937 and THP-1 cells, the binding of LTD4 to receptors was shown to be strongly inhibited by KIPRES and this inhibition was not affected by the presence of blood ingredients. On the other hand, a weak receptor antagonism against LTC4 and LTB4 was observed24). 2. Inhibitory Effect on Bronchoconstriction (Isolated Tissues and Animal Studies) The LTD4-induced contractions were competitively inhibited by KIPRES in isolated guinea pig trachea. KIPRES was also shown to have a potent, continuous inhibitory action against LTD4-induced bronchoconstriction reactions in guinea pigs and squirrel monkeys. On the other hand, KIPRES did not block contraction of isolated tissues induced by LTC4 (in the absence of LTC4 metabolism). Also, there was almost no inhibition of bronchoconstriction in guinea pigs induced by histamine, arachidonic acid, serotonin and acetylcholine. 24) 3. Inhibitory Effect on Antigen-Induced Bronchoconstriction KIPRES inhibited antigen-induced bronchoconstriction reactions in sensitized inbred asthmatic rats, guinea pigs and squirrel monkeys when administered intravenously or orally. 24) In overseas clinical studies, KIPRES inhibited early and late-phase bronchoconstriction due to antigen challenge by 75% and 57%, respectively. 25) 4. Inhibitory Effect on Immediate and Delayed Bronchoconstriction Reactions KIPRES inhibited antigen-induced immediate and delayed bronchoconstriction reactions in sensitized squirrel monkeys when administered orally. 24) 5. Inhibitory Effect on Anaphylactic Shock KIPRES partly inhibited anaphylactic shock induced by egg albumin in sensitized guinea pigs. 26) 6. Inhibitory Effect on the Increase of Allergen-induced Nasal Resistance (Nasal Congestion) KIPRES inhibited the increase of ovalbumin-induced nasal resistance (nasal congestion) in sensitized guinea pigs, by 55% and 85% at 1 mg/kg and 3 mg/kg (intraperitoneal treatment), respectively. 27) 7. Improvement of Pulmonary Function KIPRES improved the forced expiratory volume in 1 second and peak expiratory flow in patients with mild-tomoderate chronic bronchial asthma. 28) 8. Effect on Eosinophils 8 Kyorin Pharmaceutical Co., Ltd. KIPRES significantly reduced the sputum eosinophil to total leukocyte ratio in patients with mild-to-moderate chronic bronchial asthma, compared with placebo.29) Similarly, KIPRES significantly reduced the peripheral blood eosinophil to total leukocyte ratio in adult asthmatic patients, 28) and pediatric asthmatic patients. 30), 31) PHYSICOCHEMISTRY Nonproprietary name: Montelukast Sodium (JAN) Chemical name: Monosodium (1-{[((1R )-1-{3-[(1E )-2-(7chloroquinolin-2-yl)ethenyl]phenyl}-3-[2-(1-hydroxy1-methylethyl)phenyl]propyl)sulfanyl]methyl} cyclopropyl)acetate Molecular formula: C35H35ClNNaO3S Molecular weight: 608.17 Structural formula: 1) Knorr, B. et al.: J. Clin. Pharmacol., 39(8): 786,1999 2) Philip, G., et al.: J. Allergy Clin. Immunol., 124(4): 691, 2009 3) Philip, G., et al.: J. Allergy Clin. Immunol., 124(4): 699, 2009 4) Ohnishi, A. et al.: J. Clin. Ther. Med., 17 (4): 443, 2001 5) Bioequivalence study of montelukast (In-house data) 6) Zhao, J.J. et al.: Biopharm. Drug Dispos., 18(9):769,1997 7) Pharmacokinetics of montelukast in patients with hepatic insufficiency (In-house data) 8) Bioavailability of montelukast (In-house data) 9) Binding of montelukast with proteins (In-house data) 10) Filppula, A. M. et al.: Drug Metab. Dispos., 39(5): 904, 2011 11) Karonen, T. et al.: Br. J. Clin. Pharmacol., 73(2): 257, 2012 12) Karonen, T. et al.: Clin. Pharmacol. Ther., 88(2): 223, 2010 13) Chiba, M. et al.: Drug Metab. Dispos., 25(9):1022,1997 14) Friedman, E. et al.: Clin. Pharmacol. Ther., 79(2):72, 2006 15) Balani, S. K. et al.: Drug Metab. Dispos., 25 (11): 1282, 1997 16) Holland, S. et al.: Clin. Pharmacol. Ther., 63(2):231,1998 17) Malmstrom, K. et al.: Am. J. Ther., 5(3):189, 1998 18) Schwartz, J. et al.: Clin. Pharmacol. Ther., 61(2):162,1997 19) Depre, M. et al.: J. Clin. Pharmacol., 39(9):941,1999 20) Van Hecken, A. et al.: J. Clin. Pharmacol., 39(5):495,1999 CO2Na H Cl REFERENCES N S 21) Miyamoto, T. et al.: J. Clin. Ther. Med., 17 (4): 519, 2001 22) Okubo, K. et al.: Allergol. Int., 57(3): 247, 2008 23) Okubo, K. et al.: Allergol. Int., 57(4): 383, 2008 OH CH3 CH3 Description: Montelukast Sodium occurs as a white to pale yellow-white powder. It is very soluble in methanol and in ethanol (99,5), and freely soluble in water. It is hygroscopic. It turns yellow on exposure to light. It shows a crystal polymorphism. 24) Jones, T.R. et al.: Can. J. Physiol. Pharmacol., 73(2):191, 1995 25) Diamant, Z. et al.: Clin. Exp. Allergy, 29(1):42, 1999 26) Inhibitory effects of montelukast on anaphylactic shock (In-house data) 27) Inhibitory effects of montelukast on the increase of allergen-induced nasal resistance (nasal congestion) (In-house data) 28) Miyamoto, T. et al.: J. Clin. Ther. Med., 17 (4): 577, 2001 29) Minoguchi. K. et al.: Chest, 121 (3): 732, 2002 30) Furusyo, K. et al.: J. Clin. Ther. Med., 17 (4): 609, 2001 31) Furusyo, K. et al.: J. Clin. Ther. Med., 21 (10): 1019, 2005 Partition coefficient: Log KD=2.3±0.2 in 1-octanol/phosphate buffered system (pH7) PRECAUTIONS FOR HANDLING Storage conditions:Protect from moisture after opening the seal. PACKAGING KIPRES Tablets 5 mg: PTP: 28 Tablets (14 Tablets x 2) 100 Tablets (10 Tablets x 10) 140 Tablets (14 Tablets x 10) KIPRES Tablets 10mg: PTP: 28 Tablets (14 Tablets x 2) 100 Tablets (10 Tablets x 10) 140 Tablets (14 Tablets x 10) 420 Tablets (14 Tablets x 30) 500 Tablets (10 Tablets x 50) KIPRES OD Tablets 10mg: Blister sheet 60 Tablets (10 Tablets x 6) 200 Tablets (10 Tablets x 20) REQUEST FOR LITERATURE SHOULD BE MADE TO: A request for in-house data mentioned in the References can also be made to the following. Kyorin Pharmaceutical Co, Ltd. Drug Information Center 6, Kanda surugadai 4-chome, Chiyoda-ku, Tokyo 101-8311, Japan TEL: 0120-409-341 (Toll-free) 9:00 to 17:30 (Monday through Friday exclusive of national holidays) Manufactured and marketed by: Kyorin Pharmaceutical Co., Ltd. 6, Kanda surugadai 4-chome, Chiyoda-ku, Tokyo 101-8311, Japan