Japrolox

Loxoprofen sodium.

Each tablet contains 68.1 mg of loxoprofen sodium (60 mg as anhydrous).
Sodium loxoprofen, synthesized and developed by Sankyo company, Limited, is a new non-steroidal analgesic and anti-inflammatory drug in the phenylpropionic acid group. This drug is rapidly absorbed from the gastrointestinal tract and shows excellent analgesic and anti-inflammatory effects, while this drug is characterized by its relatively lower toxicity to the gastrointestinal tract than other non-steroidal analgesic and anti-inflammatory drugs because it is a prodrug showing effects after conversion to active compounds in the body.
Discrimination Code: SANKYO 157.
Generic name: Loxoprofen sodium.
Chemical name: Sodium 2-[P-(2-oxocyclopentylmathyl)phenyl]propionate dehydrate.
Molecular formula: C₁₅H₁₇NaO₃.2H₂O

PHARMACOLOGY: JAPROLOX TABLETS has excellent analgesic and anti-inflammatory effect, and its analgesic effect is specifically powerful. This drug has pharmacological characteristics such as a relatively lower toxicity to the gastrointestinal tract than other non-steroidal analgesic and anti-inflammatory drugs because it is the prodrug showing the effect after absorption from the gastrointestinal tract and conversion to active metabolites.
The mode of action of this drug is prostaglandin biosynthesis inhibition and its site of action is cyclooxygenase.
After oral administration, JAPROLOX TABLETS is rapidly absorbed from the digestive tract in the unchanged form causing weak irritation to the stomach mucosa, and then rapidly converted to an active metabolite, the trans-alcohol form (in SRS configuration) which potently inhibit prostaglandin biosynthesis.
Urinary excretion of JAPROLOX TABLETS is rapid and most amount of the drug administered is excreted in the unchanged form or in the glucoronic acid conjugated trans-OH form.
About 50% of the dose are excreted in the urine within 8 hours after administration.
PHARMACOKINETICS: Absorption and Metabolism: In sixteen healthy adult volunteers, JAPROLOX TABLETS was absorbed rapidly following a single 60-mg oral dose, and loxoprofen (unchanged drug) and its trans-OH form (active metabolite) were demonstrated in blood. The time to peak plasma concentration was about 30 minutes for loxoprofen and about 50 minutes for the trans-OH form, with an approximate half-life of 1 hour and 15 minutes for both compounds. (See Figure 1.)

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Drug-Metabolizing Enzymes: Loxoprofen sodium hydrate did not affect the metabolism of the various drugs that serve as the substrates for cytochrome P450 isoforms (CYP1A1/2, 2A6, 2B6, 2C8/9, 2C19, 2D6, 2E1, and 3A4), even at concentrations approximately 10 times as high as its peak plasma concentration (200 μM) in a metabolic inhibition study with human liver microsomes in vitro.
Pharmacokinetics Parameters (single dose): Absorption rate constant and elimination rate constant: See Table 1.

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Plasma protein binding rate: The plasma protein binding rate, as determined in humans (5 subjects at 1 hour after dosing of 60-mg JAPROLOX TABLETS) was 97.0% and 92.8% for loxoprofen and the trans-OH compound, respectively.
AUC (n=16, Mean ± S.E.): Loxoprofen: 6.70 ± 0.26 μg·hr/mL.
Trans-OH form: 2.02 ± 0.05 μg·hr/mL.
Excretion: JAPROLOX TABLETS is rapidly excreted in urine; it is excreted largely as glucuronate conjugates of loxoprofen and the trans-OH compound. (See Figures 2, 3 and Table 2.)

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Absorption and Excretion Following Multiple Doses: Absorption and excretion of JAPROLOX TABLETS after oral administration at 80 mg t.i.d. for 5 days in five healthy adult volunteers did not noticeably differ from those after a single oral dose; hence no evidence of accumulation.

This drug has anti-inflammatory and analgesic effect on the following diseases and symptoms: Chronic articular rheumatism, osteoarthritis, lumbago, periarthritis of the shoulder and shoulder-arm-neck syndrome.
This drug relieves pain and inflammation after operation, trauma and tooth extraction.

For general use, 60 mg of loxoprofen sodium (as anhydrous) are orally administered to adults three times a day.
For a single administration, 60-120 mg are orally given. The dosages should be adjusted according to age and symptoms.

JAPROLOX TABLETS is contraindicated in the following patients: 1.Patients with peptic ulcers [peptic ulcers may be aggravated due to reduced gastric blood flow resulting from inhibition of prostaglandin biosynthesis]. (See Careful administration under Precautions.)
2. Patients with severe blood disorders [Platelet dysfunction may occur and the abnormality may be worsened].
3. Patients with severe hepatic function disorders [Liver damage has been reported as an adverse reaction, and the patient's liver dysfunction may be aggravated].
4. Patients with severe renal impairment [Adverse reactions such as acute kidney injury, nephritic syndrome, etc. may occur].
5. Patients with severe cardiac function failure [Cardiac symptoms may be exacerbated because inhibition of prostaglandin biosynthesis in the kidneys may cause edema and an increase in circulating body fluid volume, with a consequent increase in cardiac work].
6. Patients with a history of hypersensitivity to any ingredients of JAPROLOX.
7. Patients with a history of aspirin-induced asthma (induction of asthmatic attack with non-steroidal anti-inflammatory-analgesics, etc.) [May induce an aspirin-induced asthmatic attack].
8. Women in the late stages of pregnancy [See Use in Pregnancy & Lactation].

Careful administration (JAPROLOX TABLETS should be administered with care in the following patients): (1) Patients with a history of peptic ulcers [since the use of this product may cause recurrence of ulceration].
(2) Patients with peptic ulcer associated with chronic use of nonsteroidal anti-inflammatory-analgesic agents whose clinical condition required long-term administration of this product and who are currently on misoprostol therapy [This drug must be administered with care while closely monitoring the clinical condition of patients receiving this drug continuously, because peptic ulcer maybe refractory to treatment with misoprostol, which is indicated for nonsteroidal anti-inflammatory-analgesic drug-induced peptic ulceration].
(3) Patients with or with a history of blood disorders [since adverse reactions such as hemolytic anemia are prone to occur].
(4) Patients with or with a history of hepatic function disorder [because exacerbation or recurrence of the hepatic function disorder have been reported with the use of JAPROLOX TABLETS].
(5) Patients with or with a history of renal impairment [since adverse reactions such as edema, proteinuria, serum creatinine elevation or hyperkalemia have been reported with the use of JAPROLOX TABLETS].
(6) Patients with cardiac dysfunction [See CONTRAINDICATIONS].
(7) Patients with a history of hypersensitivity.
(8) Patients with bronchial asthma [as the disease state may be exacerbated].
(9) Patients with colitis ulcerative [as the disease state may be exacerbated].
(10) Patients with Crohn's disease [as the disease state may be exacerbated].
(11) Elderly subjects [See Use in the Elderly as follows].
Important Precautions: (1) It is important to note that treatment with anti-inflammatory-analgesic agents is a symptomatic treatment, not a causal treatment.
(2) The following should be considered when using this product in the management of chronic disease (rheumatoid arthritis, osteoarthritis): 1) Patients receiving long-term medication should be followed by periodic laboratory examinations (e.g., urinalysis, hematological examination, liver function tests). If any abnormality is noted, appropriate measures such as dosage reduction or withdrawal should be taken.
2) Therapies other than drug treatment must also be considered.
(3) The following should be considered in using this product in the management of acute diseases: 1) The proper dosage regimen, depending on the degree of acute inflammation, pain and fever, should be determined. 2) Long-term use of the same drug(s) must be avoided in principle. 3) If any causal treatment is available, should be undertaken preferentially. Aimless treatment with JAPROLOX TABLETS should be avoided.
(4) The patient's clinical condition should be closely observed with caution against the development of adverse reactions. As an excessive decrease in body temperature, collapse, coldness of limbs, etc. may be manifested in patients using this product; the clinical status must be carefully observed after administration of the drug especially in elderly patients with a high-grade fever or patients with a debilitating disease.
(5) JAPROLOX TABLETS may mask the signs and symptoms of infections. Therefore, an appropriate antibiotic should be used in combination to treat inflammation due to infection, and the patient should be closely observed and JAPROLOX TABLETS administered with care.
(6) It is recommended to avoid the concomitant use of other anti-inflammatory-analgesic agents with JAPROLOX TABLETS.
OTHER PRECAUTIONS: It has been reported that temporary sterility is observed in women receiving long-term NSAID therapy.
Use in Children: The safety of this drug in low-birth-weight infants, newborn infants, infants and toddlers, children and adolescents have not been established.
Use in the Elderly: In elderly patients, pay special attention to adverse reactions. Careful administration is necessary; for example, care should be taken to administer the individual minimum effective dose.
In as much as adverse reactions are likely to occur in elderly patients, this product should be used with caution, e.g., starting at a low dose, while closely observation of the patient's condition (see Important Precautions as previously mentioned).

(1) This product should be administered to women who are or are possibly pregnant only when the anticipated therapeutic benefits are considered to outweigh any potential risk. If such administration is deemed necessary, caution should be exercised such as limiting to the minimum effective use and monitoring amniotic fluid as necessary. Renal impairment and decreased urine output in foetuses as well as accompanying oligohydramnios have been reported following use of cyclooxygenase inhibitors (oral dosage form or suppository) in pregnant women.
(2) This drug should not be used in women in the late stages of pregnancy. [Delayed parturition has been reported in an animal study (in rats).]
(3) Fetal arterial vasoconstriction has been reported in a study on rats receiving the drug in the late stages of gestation.
(4) Administration of this drug to nursing mothers should be avoided. If administration of this drug is judged to be essential, nursing should be discontinued. [Preclinical studies have showed that loxoprofen is excreted into milk in rats.]

(Including reports on adverse reactions the incidence of which cannot be calculated.)
Adverse reactions to this drug were reported in 409 (3.03%) of 13,486 patients treated. The major adverse reactions reported were gastrointestinal symptoms (Stomach discomfort, abdominal pain, nausea and/or vomiting, anorexia, etc.: 2.25%); edema (0.59%); rash, urticarial, etc. (0.21%); and sleepiness (0.10%).
[At the end of reexamination period and at the latest approval of indications].
(1) Clinically significant adverse reactions (incidence unknown): 1) Shock and anaphylaxis: Shock and anaphylaxis (decreased blood pressure, urticaria, edema of the larynx, dyspnea, etc.) have been reported with the use of this product.
Patients should be carefully observed during treatment. If any abnormal symptoms occurs in patient being treated with this product, the drug should be discontinued and appropriate therapies should be initiated immediately.
2) Agranulocytosis, hemolytic anemia, leukopenia and thrombocytopenia: Agranulocytosis, hemolytic anemia, leukopenia, and thrombocytopenia have been reported with the use of this product. Patients should be carefully followed by hematological examination, etc. during treatment. If any abnormal symptoms occurs in a patient being treated with this product, the drug should be discontinued and appropriated therapies should be initiated immediately.
3) Toxic epidermal necrolysis (TEN), oculomucocutaneous syndrome (Stevens-Johnson syndrome) and erythema multiforme: Toxic epidermal necrolysis, oculomucocutaneous syndrome and erythema multiforme have been reported. Patients should be carefully monitored during treatment. If any abnormal symptoms occur in patient being treated with this product, the drug should be discontinued immediately and appropriate measures instituted.
4) Acute kidney injury nephrotic syndrome and interstitial nephritis: Acute kidney injury, nephrotic syndrome and interstitial nephritis have been reported with the use of this product. Patients should be carefully observed during treatment. If any abnormal symptoms occurs in patient being treated with this product, the drug should be discontinued and appropriate therapies should be initiated immediately. This product should be used with special caution in such patients because hyperkalemia may appear in association with acute renal failure.
5) Cardiac failure congestive: Cardiac failure congestive has been reported with the use of this product. Patients should be carefully observed during treatment. If any abnormal symptoms occur in patient being treated with this drug, the drug should be discontinued and appropriate therapies should be initiated immediately.
6) Interstitial pneumonia: Interstitial pneumonia with manifestations of fever, cough, dyspnea, chest X-ray abnormalities, and eosinophilia have been reported with the use of this product. If these signs/findings are observed in patient being treated with this drug, the drug should be discontinued and appropriate therapies such as corticosteroid medication, should be initiated immediately.
7) Gastrointestinal bleeding: Serious peptic ulceration or gastrointestinal bleeding from the small intestine and/or large intestine, e.g., hematemesis, melena and hematochezia, and consequent shock has been reported with the use of this product. Patients should be carefully observed during treatment and, if any abnormal symptoms occur in a patient being treated with this drug, the drug should be discontinued and appropriate therapies should be initiated immediately.
8) Gastrointestinal perforation: Gastrointestinal perforation has been reported with the use of this drug. If any symptoms including, epigastric pain, abdominal pain, etc. are noted, in a patient being treated with JAPROLOX TABLETS, the drug should be discontinued and appropriate therapies should be initiated immediately.
9) Stenosis and/or obstruction of the small intestine and/or large intestine: Stenosis and/or obstruction with ulcer of the small intestine and/or large intestine have been reported with the use of JAPROLOX TABLETS. Patients should be carefully observed during treatment. If any symptoms including nausea and/or vomiting, abdominal pain, abdominal distension, etc. are noted in a patient being treated with JAPROLOX TABLETS, JAPROLOX TABLETS should be discontinued and appropriate therapies should be initiated immediately.
10) Hepatic function disorder and jaundice: Hepatic function disorder including jaundice, increased serum levels of AST (GOT), ALT (GPT) and ϒ-GTP or fulminant hepatitis have been reported with the use of this drug. Patients should be carefully observed during treatment, and, if any abnormal symptoms occur in patient being treated with this product, the drug should be discontinued and appropriate therapies should be initiated.
11) Asthmatic attack: Acute respiratory disorders such as asthmatic attack have been reported with the use of this product. Patients should be carefully observed during treatment, and, if any abnormal symptoms occur in a patient being treated with this product, the drug should be discontinued and appropriate therapies should be initiated immediately.
12) Aseptic meningitis: Aseptic meningitis (fever, headache, nausea and/or vomiting, nuchal rigidity, clouding of consciousness, etc.) has been reported with the use of this product. Patients should be carefully observed during treatment, and, if any abnormal symptoms occur in a patient being treated with this drug, the drug should be discontinued and appropriate therapies should be initiated immediately. (In particular, the adverse event is likely to occur in the patients with systemic lupus erythematosus or mixed connective tissue disease.)
13) Rhabdomyolysis: Rhabdomyolysis has been reported with the use of JAPROLOX TABLETS. Patients should be carefully observed during treatment. If any symptoms including myalgia, weakness, increased CK (CPK) and increased myoglobin in blood and urine, etc. are noted in a patient being treated with this drug, the drug should be discontinued and appropriate therapies should be initiated. This product should be used with special caution in such patients because acute kidney injury may appear in association with rhabdomyolysis.
(2) Clinically significant adverse reactions reported in association with the use of other non-steroidal anti-inflammatory-analgesic drugs: Aplastic anemia: Aplastic anemia has been reported in association with the use of other non-steroidal anti-inflammatory-analgesic drugs.
Other adverse reactions: See Table 3.

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Precautions for Co-administration (JAPROLOX TABLETS should be co-administered with care when administered with the following drugs). (See Table 4.)

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When JAPROLOX TABLETS are dispensed, patients should be instructed to remove each tablet from the PTP blister package before taking the drug. [It has been reported that accidental ingestion of the blister package can lead to esophageal mucosal injury and subsequent perforation caused by the pointed corner of the package, resulting in serious complications such as mediastinitis.]

JAPROLOX TABLETS may be kept at room temperature (below 30°C).

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

M01AE - Propionic acid derivatives ; Used in the treatment of inflammation and rheumatism.

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