Brexin®

β-Cyclodextrin and Piroxicam Tablets


NAME OF THE DRUG
Generic Name: β-Cyclodextrin and Piroxicam Tablets
Trade Name: Cycladol®
English Name: β-Cyclodextrin and Piroxicam Tablets
Chinese Phonetic Alphabets: Xidi Biluoxikang Pian
Active ingredients as well as their chemical names: 4-hydroxy-2-methyl-N-2-piridinyl-1,2-
benzothiazine-3-carboxamide-1,1-dioxide-β-cyclodextrin
Structural formula:
Molecular Formula: C15H13N3O4S
Molecular Weight: 331.35
PROPERTIES

lemon yellow hexahedral scored tablets, deep median scoring.
PHARMACOLOGY AND TOXICITY PROPERTIES

β-Cyclodextrin and Piroxicam is an non-steroidal anti-inflammatory drug obtained by the
complexation of piroxicam with β-cyclodextrin. The active ingredient is Piroxicam, which strongly
inhibits the activation of enzyme synthesising of prostaglandin.
β-cyclodextrin is a cyclic oligosaccharide derived by enzymatic hydrolysis of common starch. Due
to its particular chemical structure, β-cyclodextrin can form inclusion complexes (molecular
encapsulation) with different drugs, thus improving some of their properties, such as solubility,
stability and bioavailability.
Toxicology
Acute toxicity
LD50 (rat):
298 mg/kg (oral); >214 mg/kg (rectal) Subacute toxicity Monkeys (28 days, oral): 1.2-4.0 mg/kg/day were well tolerated; 12-36 mg/kg/day: occurrence of gastric lesions, significant at the highest dosage only. Chronic toxicity Rats (26 weeks, oral): 0.6 mg/kg/day: were well tolerated; 1.9 and 6.0 mg/kg/day: signs of gastric and renal toxicity. Anaemia, leucocytosis, neutrophilia and renal, splenic and gastro-enteric lesions disappeared after 8 weeks restoration period.
Reproductive toxicity
The studies carried out in some animal species (rabbits and rats) showed no embryo-foetal toxicity
and teratogenesis, and no action on fertility, reproductive function and pregnancy.
Mutagenicity and carcinogenicity
In vitro and in vivo tests did not show any evidence of mutagenic or carcinogenic effects or any
interference on the immune system.
PHARMACOKINETIC PROPERTIES
After β-Cyclodextrin and Piroxicam oral administration, only the active ingredient (piroxicam) is
absorbed, and not the complex as is.
Studies on healthy volunteers demonstrated that, after single oral administration at equivalent doses
(20 mg as piroxicam), the onset of the piroxicam plasma peak was reached earlier with β-
Cyclodextrin and Piroxicam (within 30-60 minutes, compared to 2 hours with plain piroxicam by
oral route, and within 2 hours, compared to 6-7 hours with plain piroxicam by rectal route).
The elimination parameters, Kel and half-life, do not change compared to plain piroxicam, as
complexation with β-cyclodextrin only affects absorption and not elimination kinetics.
Urinary excretion of the active ingredient over 72 hours, for all β-Cyclodextrin and Piroxicam
formulations and plain piroxicam, is about 10% of the administered dose.
β-cyclodextrin as is, after oral administration of the complex, has not been detected either in blood
or in urine. Metabolism of β-cyclodextrin occurs in the colon by intestinal microflora to linear
dextrins, maltose and glucose.

THERAPEUTIC INDICATIONS
Treatment of pain and inflammatory conditions in
1. Rheumatic diseases (.i.e.rheumatoid arthritis, osteoarthritis etc…); 2. Musculo-skeletal disorders (i.e. tendinitis, bursitis, post-traumatic pain, etc…); 3. Post-operative pain; 4. Dental pain; 5. Headache; 6. Primary dysmenorrhoea.
POSOLOGY AND METHOD OF ADMINISTRATION
Usual dosage for Adult: Oral administration, one Tablet per day (20 mg of Piroxicam).
SIDE EFFECTS
1. Gastrointestinal symptoms are the most common side effects and include: nausea, gastric disturbances, constipation, diarrhoea, flatulence, epigastric pain, anorexia. Rare cases of gastric ulcer, with or without bleeding, or perforation. 2. Other hypersensitivity reactions (rash), headache, dizziness, somnolence, discomfort, tinnitus, hearing loss, asthenia, change of blood parameters (decrease of haemoglobin and haematocrit, increase of blood urea nitrogen). 3. Seldom vomiting, allergic oedema of hands and face, increase of skin photosensitivity, sight disturbances, aplastic or haemolytic anaemia, pancytopenia, platelets decrease, Schoenlein-Henoch's purpura, eosinophilia. 4. Rare cases of pancreatitis have been reported. Some cases of haematuria, dysuria, acute renal failure, water retention (generally occurring as oedema of the lower limbs), or cardiovascular disturbances (hypertension, decompensation) have been reported. In sporadic cases the following effects occurred: epistaxis, haematemesis, melena, gastrointestinal bleeding, mouth dryness, multiform erythema, ecchymosis, skin desquamation, sweating, hypoglycaemia, hyperglycaemia, body weight changes, erethism, insomnia, depression, Stevens Johnson's syndrome, Lyell's syndrome, agranulocytosis, bladder disorder, shock and warning symptoms, acute heart failure,
stomatitis, hair loss, impairment of nails growth.
Patients should promptly inform their doctor or pharmacist about any side effect not described in
the present package insert.
CONTRAINDICATIONS
1. Hypersensitivity toβ-Cyclodextrin and Piroxicam or any component. 2. The use of β-Cyclodextrin and Piroxicam should be avoided in patients with gastro- intestinal ulcer, gastritis, dyspepsia, severe hepatic and renal diseases, severe heart failure, severe hypertension, severe blood diseases or haemorrhagic diathesis. 3. There is a potential cross-sensitivity with acetylsalicylic acid and other NSAIDs and thus β-Cyclodextrin and Piroxicam should not be given to patients in whom acetylsalicylic acid or other NSAIDs have induced asthma, rhinitis, nasal polyposis, angioedema or urticaria. 4. The use of the product is contra-indicated during ascertained or suspected pregnancy, during breast-feeding and in children.
PRECAUTIONS
1. β-Cyclodextrin and Piroxicam must be used under strict medical control in patients with a medical history of disorders of the upper gastrointestinal tract. 2. Particular caution should be adopted in patients with cardio-vascular insufficiency, hypertension, reduced hepatic and renal function, renal hypoperfusion, history or presence of blood diseases, in patient treated with diuretics and elderly patients. In all these cases, it is advisable to periodically monitor clinical and laboratory parameters, especially during prolonged treatment. 3. For its interaction with arachidonic acid metabolism, the drug may induce bronchospasm attacks and possibly shock and other allergic reactions in asthmatic or predisposed patients. 4. During treatment, some patients showed increase of blood urea nitrogen, but not exceeding certain limits. These values become normal again after therapy discontinuation. 5. It is advisable to frequently check blood glucose levels in diabetic patients. 6. It is advisable to frequently check prothrombin time in subjects concomitantly treated with anticoagulant dicumarine derivatives. 7. Piroxicam, like other NSAIDs, decreases platelet aggregation and prolongs the bleeding time; this must be taken into account when blood tests are performed and when the patient is concomitantly treated with inhibitors of platelet aggregation. 8. As some ocular changes were observed during therapy with NSAIDs, in case of prolonged treatment, it is advisable to perform periodical ophthalmological controls. 9. Increase in hepatic function parameters, jaundice with rare cases of fatal hepatitis have been reported. Piroxicam therapy should be discontinued when clinical signs and symptoms of hepatic disturbances occur. 10. β-Cyclodextrin and Piroxicam could reduce the alertness, so β-Cyclodextrin and Piroxicam probably influence driving or action which need fast reaction. 11. β-Cyclodextrin and Piroxicam should be avoided before or after drinking alcohol.
PREGNANCY AND LACTATION
The animal trail shows that β-Cyclodextrin and Piroxicam inhibit the synthesize and release of
prostaglandin. The possibility of dystocia will ascend if terminal pregnancy animal use the product.
So the use of the product is contra-indicated during ascertained or suspected pregnancy, and during
breast feeding.
EFFECT ON CHILDREN
The use of the product is contra-indicated in children.
EFFECT ON ELDER PEOPLE
In elderly patients, for whom dosage must be carefully established by the physician, it might be
necessary a dose reduction (half a tablet) and to limit the treatment duration. A prolonged
administration of doses higher than 30 mg/day enhances the risk of gastrointestinal side effects.
Or it should follow advice of the physician.
To divide the tablet: put it on a flat surface with scoring line upwards.
By gently pressing with your thumb, the tablet is broken into two equal parts.

DRUG INTERACTIONS
1. The product interacts with acetylsalicylic acid, other non steroidal anti-inflammatory substances and with substances inhibiting platelet aggregation, so do not recommend to combine with other non steroidal antiinflammatory substances. 2. Concomitant administration with lithium product brings enhancements in lithium plasma 3. Due to the high protein-binding of piroxicam, displacement of other protein-bound drugs might be happened. Patients receiving other protein-bound drugs must be closely monitored, dosage adjustment is required if necessary. 4. Piroxicam absorption was mildly increased after concomitant with cimetidine. However, 5. Other possible interactions may occur: a. Piroxicam may decrease the efficacy of diuretics and anti-hypertensive drugs. b. In case of concomitant administration of potassium product, or diuretics, there is an additional risk of a rise in potassium serum concentrations (hyperkalemia). c. Concomitant administration of glucocorticoids may increase the risk of gastrointestinal bleeding. 6. The concomitant use with quinolone derivatives is not recommended.

OVERDOSAGE
In the event of overdose, supportive and symptomatic treatment is indicated.
STRENGTHEN
Each tablet containing 191.2mg of β-Cyclodextrin and Piroxicam (corresponding to 20mg
Piroxicam).
SHELF LIFE
3 years.
PACKAGES
PVC/PVDC/Al opaque blisters, 6 tablets/box and 10 tablets/box.
STORAGE
Store in room temperature.

APPROVAL NUMBER

LICENSE HOLDER
Chiesi Famaceutici S.P.A
Via Palemo 26/A Parma Italy
+39-0521 279726

MANUFACTURER
Chiesi Famaceutici S.P.A
Via San Leonardo, 96, Parma

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