Docso

Rx                DOCSO

COMPOSITION:

DOCSO 1 TAB

Each film coated tablet contains:

Doxophylline IP       400mg

DESCRIPTION:

Doxophylline [7-(1,3-dioxolane-2-methyl) theophylline] is a molecule that belongs to the family of methylxanthines. Its therapeutic activity has been evidenced in experimental studies made in animals, and in clinical trials made with asthmatic patients or individuals with COPD; it has demonstrated to have bronchodilator activity superior to that of theophylline in spite of its inferior affinity for adenosine receptors A1 and A2. Its use has been effective in the improvement of vital capacity, PEF and particularly in FEV1, in which it achieves a significant reduction of the residual volume. It reduces the rate of exacerbations and the use of β2 rescue schemes. The trials made in asthmatic adults have shown better results to those of theophylline to relieve the states of bronco-obstruction with less adverse effects.

The more favorable safety profile of Doxophylline is seen both in patients with Asthma, and in patients with COPD. Indeed, Doxophylline has shown a better tolerability than theophylline and aminophylline (Bossi and Berni, 1989; Goldstein and Chervinsky, 2002; Marino et al. 1988; Melillo et al. 1989).

A novel methylxanthine Doxophylline, are currently an interesting option to consider in our countries as mono therapy for the management of mild persistent asthma and COPD, but especially for the combination therapy with inhaled steroids in the management of moderate persistent forms of asthma.

PHARMACODYNAMICS:

Mechanism of Action

Doxofylline is a novel bronchodilator xanthine that differs from theophylline by a dioxalane group in position 7. Like theophylline, Doxofylline s mechanism of action is related to the inhibition of phosphodiesterase activities. However, in contrast with theophylline, Doxofylline appears to have a decreased affinity toward adenosine A1 and A2 receptors which may account for the better safety profile of the drug. Doxofylline is reported to inhibit platelet activating factor (PAF) induced

brochoconstriction and subsequent generation of thromboxane A2 (TXA2). It is also reported to inhibit PAF induced pleural exudation and generation of leukotriene C4 (LTC4) substances. This mehtylxanthine-induced inhibition of inflammatory response is a useful action in the therapy of asthma.

PHARMACOKINETICS

Absorption

(A) Bioavailability: Oral, Tablets: 62.6%

(B) Therapeutic Drug Concentration

(1) Chronic Bronchitis, 8 to 20 mcg / ml

(C) Time to Peak Concentration: Oral, tablets: 1.19 hours

 (a)The steady state is reached within 6 hr at 9.43 mcg/ml

 (D)Area Under the Curve

 (1) 69.5 h X mcg/ml, oral administration

 Distribution

(1) Protein Binding: 48%;

(2) Distribution Half Life: 0.19 hrs;

(3) Volume of Distribution: 1 L / kg

Metabolism

(A) Metabolism sites and Kinetics: Liver: greater than 90%

(B) Metabolites: Hydroxyehtyltheophylline (inactive)

 Excretion

(A) Kidney: Less than 4% of an administered dose of doxofylline is excreted unchanged in the urine.

(B) Total Body clearance: 444 to 806 mcg/mL

(C) Elimination Half-Life: Parent compound: 7 to 10 hrs (Oral)

Indications:

Doxofylline is used for the treatment of :

- Bronchial Asthma

- Chronic Obstructive Pulmonary Diseases

CONTRAINDICATIONS:

DOCSO is contraindicated in individual who have shown hypersensitivity to its components. It is also contraindicated in patients with acute myocardial infarction, hypotension and in lactating women.

WARNING AND PRECAUTIONS:

Use with caution in patients with hypertension, heart disease, hypoxemia, hyperthyroidism, chronic right ventricular failure, congestive heart failure, liver disease, renal disease, in those with history of peptic ulcer, and in the elderly. Frequently, patients with congestive heart failure have markedly prolonged drug plasma levels following discontinuation of the drug.

The half-life of xanthine derivatives is influenced by a number of known variables. It may be prolonged in patients with liver disease, in patients with congestive heart failure, in those affected with chronic obstructive lung disease or concomitant infections, and in those patients taking certain other drugs (erythromycin, troleandomycin, lincomycin and other antibiotics of the same group, allopurinol, cimetidine, propanolol, and antiflu vaccine). In these cases, a lower dose of doxofylline may be needed.

 Phenytoin, other anticonvulsants and smoking may cause an increase in clearance with a shorter mean half-life: in these cases higher doses of doxofylline may be needed. Laboratory monitoring of plasma concentration of doxofylline is recommended in all the above situations.

USE IN SPECIAL POPULATIONS

Pregnancy

Animal reproduction studies indicate that Doxophylline does not cause fetal harm when administered to pregnant animals nor can affect reproduction capacity. However, since there is limited experience in human during pregnancy, xanthines should be given to pregnant women only if clearly needed.

Lactation

Doxophylline is contraindicated in nursing mothers.

Pediatrics

The recommended dosage of Doxophylline is 12mg/kg daily, divided into 2 doses .In case of unsatisfactory response it can be increased upto 18mg/kg daily under medical supervision.

Geriatrics

The dosage (800mg/day)may be decreased according to medical prescription in the very elderly patients with concomitant cardiovascular ,hepatic ,renal ,and gastric diseases ,to half (1/2)tablet b.i.d 

DRUG INTERACTIONS:

Doxophylline should not be administered together with other xanthine derivatives.Toxic synergism with ephedrine has been documented for xanthine like other xanthines, concomitant therapy with erythromycin troleanodomycin  lincomycin, clindamycin ,allopurinol, cimetidine ,ranitidine, propranolol and anti-flu vaccine may decrease the hepatic clerance of xanthines causes an increase in blood vessels. No evidence of relationship between Doxophylline serum concentration and toxic events has been reported.

ADVERSE EFFECTS:

After xanthine administration, nausea, vomiting, epigastric pain, cephalagia (headache), irritability, insomnia, tachycardia, extrasystole, tachypnoea and, occasionally, hyperglycaemia and albuminuria may occur.

If a potential oral overdose is established, the patient may present with seizures; these symptoms could be the first sign of intoxication. Adverse reactions may cause the withdrawal from treatment; a lower dose re challenge may start only after the advice of a physician.

DOSAGE AND ADMINISTRATION:

  Adults: Pulmosan 400 mg 1 Tablet twice daily.

  The dosage may be increased to t.i.d. according to the prescribing physician.

  The dosage (800 mg/ day ) may be decreased according to medical prescription        in the  Very elderly patients with concomitant cardiovascular, hepatic, renal and  gastric disease, to ½ tablet b.i.d.

 Child: The recommended dosage of Doxofylline is 12 mg / kg daily, divided into 2 doses. In case of unsatisfactory response it can be increased up to 18mg / kg daily under medical supervision

Dosage	Weight of the Child
	10 Kg	15 Kg	20 Kg	25 Kg	30 Kg	35 Kg	40 Kg
6-mg/kg b.i.d.	3 ml	4.5 ml	6 ml	7.5 ml	9 ml	10.5 ml	12 ml
Total Daily Dose	6 ml	9 ml	12 ml	15 ml	18 ml	21 ml	24 ml

OVERDOSAGE

Although no major arrhythmias have been documented with the occurrence of major cardiac rhythm disturbances cannot be excluded in case of over dosage of xanthine compounds. If a potential oral overdose is established, the patient may present with seizures; these symptoms could be the first sign of intoxication. Adverse reactions may cause withdrawal from treatment. A lower dose re-challenge may be started only after the advice of the physician. There is no specific antidote; it is suggested that the management principles should be instituted according to symptomatic relief of cardiocirculatory shock.

STORAGE AND HANDLING INSTRUCTIONS

Store in a cool dry place, protect from light.

PACKAGING INFORMATION

DOCSO is available in a strip of 10 Tablets.

Each box of DOCSO contains 10 X 10’s