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.
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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CURRICULUM VITAE Texas A&M Health Science Center (TAMU 1266) E-mail: [email protected] EDUCATION: University of Houston, Houston, Texas Professor, Department of Health Policy and Management, College of Rural Public Health, Texas A&M Health Science Center, College Station, Texas. Scientific Advisor, U.S. Health Economics, Oxford Outcomes, Ltd., Morristown, New Professor, De