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Esmolol Hydrochloride 10 mg/ml and 250 mg/ml injections are clear, colourless to slightly yellow, sterile 10 ml solutions.
BREVIBLOC (esmolol HCl) is a beta1-selective (cardioselective) adrenergic receptor blocking agent with rapid onset, a very short duration of action, and no significant intrinsic sympathomimetic or membrane stabilising activity at therapeutic dosages. Its elimination half-life after intravenous infusion is approximately 9 minutes. BREVIBLOC inhibits the beta1 receptors located chiefly in cardiac muscle, but this preferential effect is not absolute and at higher doses it begins to inhibit beta2 receptors located chiefly in the bronchial and vascular musculature
BREVIBLOC (esmolol HCl) is rapidly metabolised by hydrolysis of the ester linkage, chiefly by the esterases in the cytosol of red blood cells and not by plasma cholinesterases or red cell membrane acetylcholinesterase. Total body clearance in man was found to be about 20 L/kg/hr, which is greater than cardiac output; thus the metabolism of BREVIBLOC is not limited by the rate of blood flow to metabolising tissues such as the liver or affected by hepatic or renal blood flow. BREVIBLOC has a rapid distribution half-life of about 2 minutes and an elimination half-life of about 9 minutes.
Using an appropriate loading dose, steady-state blood levels of BREVIBLOC for dosages from 50 - 300 mcg/kg/min (0.05-0.3 mg/kg/min) are obtained within five minutes. (Steady state is reached in about 30 minutes without the loading dose). Steady-state blood levels of BREVIBLOC increase linearly over this dosage range and elimination kinetics are dose-independent over this range. Steady-state blood levels are maintained during infusion but decrease rapidly after termination of the infusion. Because of its short half-life, blood levels of BREVIBLOC can be rapidly altered by increasing or decreasing the infusion rate and rapidly eliminated by discontinuing the infusion.
Consistent with the high rate of blood-based metabolism of BREVIBLOC, less than 2% of the medicine is excreted unchanged in the urine. Within 24 hours of the end of infusion, approximately 73-88% of the dosage has been accounted for in the urine as the acid metabolite of BREVIBLOC.
Metabolism of BREVIBLOC results in the formation of the corresponding free acid and methanol. The acid metabolite has been shown in animals to have about 1/1500th the activity of esmolol and in normal volunteers its blood levels do not correspond to the level of beta-blockade. The acid metabolite has an elimination half-life of about 3.7 hours and is excreted in the urine with a clearance approximately equivalent to the glomerular filtration rate. Excretion of the acid metabolite is significantly decreased in patients with renal disease, with the elimination half-life increased to about ten-fold that of normals, and plasma levels considerably elevated.
Methanol blood levels, monitored in subjects receiving BREVIBLOC for up to 6 hours at 300 mcg/kg/min (0.3 mg/kg/min) and 24 hours at 150 mcg/kg/min (0.15 mg/kg/min), approximated endogenous levels and were less than 2% of levels usually associated with methanol toxicity.
BREVIBLOC has been shown to be 55% bound to human plasma protein, while the acid metabolite is only 10% bound.
Clinical pharmacology studies in normal volunteers have confirmed the beta blocking activity of BREVIBLOC (esmolol HCl), showing reduction in heart rate at rest and during exercise, and attenuation of isoproterenol-induced increases in heart rate. Blood levels of BREVIBLOC have been shown to correlate with extent of beta blockade. After termination of infusion, substantial recovery from beta blockade is observed in 10-20 minutes.
In human electrophysiology studies, BREVIBLOC produced effects typical of a beta blocker: a decrease in the heart rate, increase in sinus cycle length, prolongation of the sinus node recovery time, prolongation of the AH interval during normal sinus rhythm and during atrial pacing, and an increase in antegrade Wenckebach cycle length.
In patients undergoing radionuclide angiography, BREVIBLOC, at dosages of 200 mcg/kg/min (0.2 mg/kg/min), produced reductions in heart rate, systolic blood pressure, rate pressure product, left and right ventricular ejection fraction and cardiac index at rest, which were similar in magnitude to those produced by intravenous propranolol (4 mg). During exercise, BREVIBLOC produced reductions in heart rate, rate pressure product and cardiac index which were also similar to those produced by propranolol, but produced a significantly larger fall in systolic blood pressure. In patients undergoing cardiac catheterisation, the maximum therapeutic dose of 300 mcg/kg/min (0.3 mg/kg/min) of BREVIBLOC produced similar effects, and, in addition, there were small, clinically insignificant, increases in the left ventricular and diastolic pressure and pulmonary capillary wedge pressure. At thirty minutes after the discontinuation of BREVIBLOC infusion, all the haemodynamic parameters had returned to pretreatment levels.
The relative cardioselectivity of BREVIBLOC was demonstrated in 10 mildly asthmatic patients. Infusions of BREVIBLOC [100, 200 and 300 mcg/kg/min (0.1, 0.2 and 0.3 mg/kg/min)] produced no significant increases in specific airway resistance compared to placebo. At 300 mcg/kg/min (0.3 mg/kg/min), BREVIBLOC produced slightly enhanced bronchomotor sensitivity to dry air stimulus. These effects were not clinically significant, and BREVIBLOC was well tolerated by all patients. Six of the patient also received intravenous propranolol, and at a dosage of 1 mg, two experienced significant, symptomatic bronchospasm requiring bronchodilator treatment. One other propranolol-treated patient also experienced dry air-induced bronchospasm. No adverse pulmonary effects were observed in patients with COPD who received therapeutic dosages of BREVIBLOC for treatment of supraventricular tachycardia (51 patients) or in perioperative settings (32 patients).
Supraventricular Tachycardia: In two multicentre, randomised, double-blind, controlled comparisons of BREVIBLOC with placebo and propranolol, maintenance doses of 50 to 300 mcg/kg/min (0.05 to 0.3 mg/kg/min) of BREVIBLOC were found to be more effective than placebo and about as effective as propranolol, 3-6 mg given by bolus injections, in the treatment of supraventicular tachycardia, principally atrial fibrillation & atrial flutter. The majority of these patients developed their arrhythmias postoperatively. About 60-70% of the patients treated with BREVIBLOC had a desired therapeutic effect (either a 20% reduction in heart rate, a decrease in heart rate to less than 100 bpm or, rarely, conversion to NSR) and about 95% of those who responded did so at a dosage of 200 mcg/kg/min (0.2 mg/kg/min) or less. The average effective dosage of BREVIBLOC was approximately 100-115 mcg/kg/min (0.1-0.115 mg/kg/min) in the two studies. Other multicentre baseline-controlled studies gave essentially similar results. In the comparison with propranolol, about 50% of patients in both the BREVIBLOC and propranolol groups were on concomitant digoxin. Response rates were slightly higher with both beta blockers in the digoxin-treated patients.
In all studies significant decreases of blood pressure occurred in 20-50% of patients, identified either as adverse reaction reports by investigators, or by observation of systolic pressure less than 90 mmHg or diastolic pressure less than 50 mmHg. The hypotension was symptomatic (mainly diaphoresis or dizziness) in about 12% of patients, and therapy was discontinued in about 11% of patients, about half of whom were symptomatic. In comparison to propranolol, hypotension was about three times as frequent with BREVIBLOC, 53% vs. 17%. The hypotension was rapidly reversible with decreased infusion rate or after discontinuation of therapy with BREVIBLOC. For both BREVIBLOC and propranolol, hypotension was reported less frequently in patients receiving concomitant digoxin.
Supraventricular Tachycardia: BREVIBLOC (esmolol HCl) is indicated for the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short term control of ventricular rate with a short-acting agent is desirable. BREVIBLOC is also indicated in noncompensatory sinus tachycardia where, in the physician's judgement, the rapid heart rate requires specific intervention. BREVIBLOC is not intended for use in chronic settings where transfer to another agent is anticipated.
Intraoperative and Postoperative Tachycardia and/or Hypertension: BREVIBLOC is indicated for the treatment of tachycardia and hypertension that occur during induction and tracheal intubation, during surgery, on emergence from anaesthesia, and in the postoperative period, when in the physician's judgement such specific intervention is indicated.
Use of BREVIBLOC to prevent such events is not recommended.
Ampoules only: Not for direct intravenous injection. BREVIBLOC is a concentrated, potent medicine, which must be diluted prior to its infusion. BREVIBLOC should not be admixed with sodium bicarbonate. BREVIBLOC should not be mixed with other medicines prior to dilution in a suitable intravenous fluid.
Note: Parenteral medicine products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit.
Dilution (Ampoules only): Aseptically prepare a 10 mg/ml infusion, by adding two 2500mg ampoules to a 500 ml container, or one 2500mg ampoule to a 250 ml container, of a compatible intravenous solution listed below, see "Compatibility with Commonly Used Intravenous Fluids". (Remove overage prior to dilution as appropriate). This yields a final concentration of 10 mg/ml. The diluted solution is stable for at least 24 hours at room temperature.
Note: Concentrations of BREVIBLOC greater than 10 mg/ml are likely to produce irritation on continued infusion (see Precautions). BREVIBLOC has, however, been well tolerated when administered via a central vein.
100 mg vial - This dosage form is prediluted to provide a ready-to-use 10 mg/ml concentration recommended for BREVIBLOC intravenous administration. It may be used to administer the appropriate BREVIBLOC loading dosage infusions by hand-held syringe while the maintenance infusion is being prepared. When using the 100 mg vial, a loading dose of 0.5 mg/kg/min for a 70 kg patient would be 3.5 ml.
In the treatment of supraventricular tachycardia, responses to BREVIBLOC usually (over 95%) occur within the range of 50 to 200 mcg/kg/min (0.05 to 0.2 mg/kg/min). The average effective dosage is approximately 100 mcg/kg/min (0.1 mg/kg/min) although dosages as low as 25 mcg/kg/min (0.025 mg/kg/min) have been adequate in some patients. Dosage as high as 300 mcg/kg/min (0.3 mg/kg/min) have been used, but these provide little added effect and an increased rate of adverse effects, and are not recommended. Dosage of BREVIBLOC in supraventricular tachycardia must be individualised by titration in which each step consists of a loading dosage followed by a maintenance dosage.
To initiate treatment of a patient with supraventricular tachycardia, administer a loading infusion of 500 mcg/kg/min (0.5 mg/kg/min) of BREVIBLOC over one minute followed by a four-minute maintenance infusion of 50 mcg/kg/min (0.05 mg/kg/min). If an adequate therapeutic effect is observed over the five minutes of drug administration, maintain the maintenance infusion dosage with periodic adjustments up or down as needed. If an adequate therapeutic effect is not observed, the same loading dosage is repeated over one minute followed by an increased maintenance infusion rate of 100 mcg/kg/min (0.1 mg/kg/min).
Continue titration procedure as above, repeating the original loading infusion of 500 mcg/kg/min (0.5 mg/kg/min) over one minute, but increasing the maintenance infusion rate over the subsequent four minutes by 50 mcg/kg/min (0.05 mg/kg/min) increments. As the desired heart rate or blood pressure is approached, omit subsequent loading doses and titrate the maintenance dosage up or down to endpoint. Also, if desired, increase the interval between steps from 5 to 10 minutes.
This specific dosage regimen has not been studied intraoperatively and because of the time required for titration, may not be optimal for intraoperative use.
The safety of dosages above 300 mcg/kg/min (0.3 mg/kg/min) has not been studied.
In the event of an adverse reaction, the dosage of BREVIBLOC may be reduced or discontinued. If a local infusion site reaction develops, an alternative infusion site should be used and caution should be taken to prevent extravasation. The use of butterfly needles should be avoided.
Abrupt cessation of BREVIBLOC in patients has not been reported to produce the withdrawal effects which may occur with abrupt withdrawal of beta-blockers following chronic use in coronary artery disease (CAD) patients. However caution should still be used in abruptly discontinuing infusions of BREVIBLOC in CAD patients.
After achieving an adequate control of the heart rate and a stable clinical status in patients with supraventricular tachycardia, transition to alternative antiarrhythmic agents such as propranolol or digoxin may be accomplished. A recommended guideline for such a transition is given below but the physician should carefully consider the labelling instructions for the alternative agent selected:
| Alternative Agent | Dosage |
|---|---|
| Propranolol hydrochloride | 10-20 mg q 4-6 h |
| Digoxin | 0.125-0.5 mg q 6 h (p.o. or i.v.) |
The dosage of BREVIBLOC should be reduced as follows:
The use of infusions of BREVIBLOC up to 24 hours has been well documented; in addition, limited data from 24-48 hours (N=48) indicate that BREVIBLOC is well tolerated up to 48 hours.
Intraoperative and Postoperative Tachycardia and/or Hypertension: In the Intraoperative and postoperative settings it is not always advisable to slowly titrate the dose of BREVIBLOC to a therapeutic effect. Therefore, two dosing options are presented: immediate control dosing and a gradual control when the physician has time to titrate.
BREVIBLOC (esmolol HCl) is contraindicated in patients with sinus bradycardia, heart block greater than first degree, cardiogenic shock, overt heart failure, bronchial asthma or other obstructive lung disease (see Warnings).
Hypotension: In clinical trials 20-50% of patients treated with BREVIBLOC (esmolol HCl) have experienced hypotension, generally defined as systolic pressure less than 90 mmHg and/or diastolic pressure less than 50 mmHg. About 12% of the patients have been symptomatic (mainly diaphoresis or dizziness). Hypotension can occur at any dose but is dose-related so that doses beyond 200 mcg/kg/min (0.2 mg/kg/min) are not recommended. Patients should be closely monitored, especially if pretreatment blood pressure is low. Decrease of dose or termination of infusion reverses hypotension, usually within 30 minutes.
Cardiac Failure: Sympathetic stimulation is necessary in supporting circulatory function in congestive heart failure, and beta blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. Continued depression of the myocardium with beta blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of impending cardiac failure, BREVIBLOC should be withdrawn. Although withdrawal may be sufficient because of the short elimination half-life of BREVIBLOC, specific treatment may also be considered. (See Overdosage). The use of BREVIBLOC for control of ventricular response in patients with supraventricular arrhythmias should be undertaken with caution when the patient is compromised haemodynamically or is taking other drugs that decrease any or all of the following: peripheral resistance, myocardial filling, myocardial contractility, or electrical impulse propagation in the myocardium. Despite the rapid onset and offset of the effects of BREVIBLOC, several cases of death have been reported in complex clinical states where BREVIBLOC was presumably being used to control ventricular rate.
Intraoperative and Postoperative Tachycardia and/or Hypertension: BREVIBLOC should not be used as the treatment for hypertension in patients in whom the increased blood pressure is primarily due to the vasoconstriction associated with hypothemia.
Bronchospastic Disease: Patients with bronchospastic diseases should, in general, not receive beta blockers. Because of its relative beta1 selectivity and tolerability, BREVIBLOC may be used with caution in patients with bronchospastic diseases. However, since beta1 selectivity is not absolute, BREVIBLOC should be carefully titrated to obtain the lowest possible effective dose. In the event of bronchospasm, the infusion should be terminated immediately; a beta2 stimulating agent may be administered if conditions warrant but should be used with particular caution as patients already have rapid ventricular rates.
Diabetes Mellitus and Hypoglycaemia: BREVIBLOC should be used with caution in diabetic patients requiring a beta-blocking agent. Beta blockers may mask tachycardia occurring with hypoglycaemia, but other manifestations such as dizziness and sweating may not be significantly affected.
Infusion concentrations of 20 mg/ml were associated with more serious venous irritation, including thrombophlebitis, than concentrations of 10 mg/ml. Extravasation of 20 mg/ml may lead to a serious local reaction and possible skin necrosis. Concentrations greater than 10 mg/ml or infusion into small veins or through a butterfly catheter should be avoided. Because the acid metabolite of BREVIBLOC is primarily excreted unchanged by the kidney, BREVIBLOC (esmolol HCl) should be administered with caution to patients with impaired renal function. The elimination half-life of the acid metabolite was prolonged ten-fold and the plasma level was considerably elevated in patients with end-stage renal disease.
Care should be taken in the intravenous administration of BREVIBLOC as sloughing of the skin and necrosis have been reported in association with infiltration and extravasation of intravenous infusions.
Catecholamine-depleting medicines, eg reserpine, may have an additive effect when given with beta blocking agents. Patients treated concurrently with BREVIBLOC and a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may result in vertigo, syncope, or postural hypotension.
A study of interaction between BREVIBLOC and warfarin showed that concomitant administration of BREVIBLOC and warfarin does not alter warfarin plasma levels. BREVIBLOC concentrations were equivocally higher when given with warfarin, but this is not likely to be clinically important When digoxin and BREVIBLOC (esmolol HCl) were concomitantlyadministered intravenously to normal volunteers, there was a 10-20% increase in digoxin blood levels at some time points. Digoxin did not affect BREVIBLOC pharmacokinetics. When intravenous morphine and BREVIBLOC were concomitantly administered in normal subjects, no effect on morphine blood levels was seen, but BREVIBLOC steady-state blood levels were increased by 46% in the presence of morphine. No other pharmacokinetic parameters were changed.
The effect of BREVIBLOC on the duration of succinylcholine-induced neuromuscular blockade was studied in patients undergoing surgery. The onset of neuromuscular blockade by succinylcholine was unaffected by BREVIBLOC, but the duration of neuromuscular blockade was prolonged from 5 minutes to 8 minutes.
Although the interactions observed in these studies do not appear to be of major clinical importance, BREVIBLOC should be treated with caution in patients being treated concurrently with digoxin, morphine, succinylcholine or warfarin.
While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.
Caution should be exercised when considering the use of BREVIBLOC and Verapamil in patients with depressed myocardial function. Fatal cardiac arrests have occurred in patients receiving both drugs. Additionally, BREVIBLOC should not be used to control supraventricular tachycardia in the presence of agents which are vasoconstrictive and inotropic such as dopamine, epinephrine, and norepinephrine because of the danger of blocking cardiac contractility when systemic vascular resistance is high.
Because of its short term usage no carcinogenicity, mutagenicity or reproductive performance studies have been conducted with BREVIBLOC.
Teratogenicity studies in rats at intravenous dosages of BREVIBLOC up to 3000 mcg/kg/min (3 mg/kg/min) (ten times the maximum human maintenance dosage) for 30 minutes daily produced no evidence of maternal toxicity, embryotoxicity or teratogenicity, while a dosage of 10 000 mcg/kg/min (10 mg/kg/min) produced maternal toxicity and lethality. In rabbits, intravenous dosages up to 1000 mcg/kg/min (1 mg/kg/min) for 30 minutes daily produced no evidence of maternal toxicity, embryotoxicity or teratogenicity, while 2500 mcg/kg/min (2.5 mg/kg/min) produced minimal maternal toxicity and increased foetal resorptions.
Although there are no adequate and well-controlled studies in pregnant women, use of esmolol during labour and delivery has been reported to cause foetal bradycardia despite termination of drug infusion. Brevibloc should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
It is not known whether BREVIBLOC is excreted in human milk, however, caution should be exercised when BREVIBLOC is administered to a nursing woman.
The safety & effectiveness of BREVIBLOC in children have not been established.
The following adverse reaction rates are based on use of BREVIBLOC in clinical trials involving 369 patients with supraventricular tachycardia and over 600 intraoperative and postoperative patients enrolled in clinical trials. Most adverse effects observed in controlled clinical trial settings have been mild and transient. The most important adverse effect has been hypotension (see WARNINGS). Deaths have been reported in post-marketing experience occurring during complex clinical states where BREVIBLOC was presumably being used simply to control ventricular rate (see WARNINGS/Cardiac Failure).
Cardiovascular - Symptomatic hypotension (diaphoresis, dizziness) occurred in 12% of patients, and therapy was discontinued in about 11%, about half of whom were symptomatic. Asymptomatic hypotension occurred in about 25% of patients. Hypotension resolved during BREVIBLOC infusion in 63% of these patients and within 30 minutes after discontinuation of infusion in 80% of the remaining patients. Diaphoresis accompanied hypotension in 10% of patients. Peripheral ischaemia occurred in approximately 1% of patients. Pallor, flushing, bradycardia (heart rate less that 50 beats per minute), chest pain, syncope, pulmonary oedema and heart block have been reported in less than 1% of patients. In two patients without supraventricular tachycardia but with serious coronary artery disease (post inferior myocardial infarction or unstable angina), severe bradycardia/sinus pause/asystole has developed, reversible in both cases with discontinuation of treatment.
Central Nervous System - Dizziness has occurred in 3% of patients; somnolence in 3%, confusion, headache, and agitation in about 2%, and fatigue in about 1% of patients. Paraesthesia, asthenia, depression, abnormal thinking, anxiety, anorexia, and lightheadedness were reported in less than 1% of patients. Seizures were also reported in less than 1% of patients, with one death.
Respiratory - Bronchospasm, wheezing, dyspnoea, nasal congestion, rhonchi and rales have each been reported in less than 1% of patients.
Gastrointestinal - Nausea was reported in 7% of patients. Vomiting has occurred in about 1% of patients. Dyspepsia, constipation, dry mouth and abdominal discomfort have each occurred in less than 1% of patients. Taste perversion has also been reported.
Skin (Infusion Site) - Infusion site reactions including inflammation and induration were reported in about 8% of patients. Oedema, erythema, skin discolouration, burning at the infusion site, thrombophlebitis, and local skin necrosis from extravasation have each occurred in less than 1% of patients.
Miscellaneous - Each of the following has been reported in less than 1% of patients: Urinary retention, speech disorder, abnormal vision, midscapular pain, rigors and fevers.
BREVIBLOC (esmolol HCl) INJECTION was tested for compatibility with ten commonly used intravenous fluids at a final concentration of 10 mg esmolol HCl per ml. BREVIBLOC INJECTION was found to be compatible with the following solutions and was stable for at least 24 hours at controlled room temperature or under refrigeration:
Dextrose (5%) Injection USP
Dextrose (5%) in Lactated Ringer's Injection
Dextrose (5%) in Ringer's Injection
Dextrose (5%) and Sodium Chloride (0.45%) Injection USP
Dextrose (5%) and Sodium Chloride (0.9%) Injection USP
Lactated Ringer's Injection USP
Potassium Chloride (40 mEq/litre) in Dextrose (5%) Injection USP
Sodium Chloride (0.45%) Injection USP
Sodium Chloride (0.9%) Injection USP
BREVIBLOC INJECTION was NOT compatible with Sodium Bicarbonate (5%) Injection USP.
Overdoses of BREVIBLOC can cause cardiac arrest. In addition, overdoses can produce bradycardia, hypotension, electromechanical dissociation and loss of consciousness. Cases of massive accidental overdoses of BREVIBLOC have occurred due to dilution errors. Some of these overdoses have been fatal while others resulted in permanent disability. Bolus doses in the range of 625 to 2500mg (12.5-50mg/kg) have been fatal. Patients have recovered completely from overdoses as high as 1.75g given over one minute or doses of 7.5g given over one hour for cardiovascular surgery. The patients who survived appear to be those, whose circulation could be supported until the effects of Brevibloc resolved.
Because of its approximately 9-minute elimination half-life, the first step in the management of toxicity should be to discontinue the BREVIBLOC infusion. Then, based on the observed clinical effects, the following general measures should also be considered:
Bradycardia: Intravenous administration of atropine or another anticholinergic medicine.
Bronchospasm: Intravenous administration of a beta2 stimulating agent and/or a theophylline derivative.
Cardiac Failure: Intravenous administration of a diuretic and/or digitalis glycoside. In shock resulting from inadequate cardiac contractility, intravenous administration of dopamine, dobutamine, isoproterenol, or amrinone may be considered.
Symptomatic Hypotension: Intravenous administration of fluids and/or pressor agents.
Store at Controlled Room Temperature (20-25°C). Freezing does not adversely affect the product, but exposure to elevated temperatures should be avoided.
Prescription medicine.
250 mg/ml 10 ml (2500mg) ampoules in boxes of 10.
10 mg/ml 10 ml vials (100 mg) in boxes of 20.
Nil.
AFT Pharmaceuticals Ltd
P O Box 33-203
Takapuna
Auckland
Ph: 0800 423 823 or 09 488 0232
Fax: 0800 423 874 or 09 488 0234
E-mail:
customer.service@aftpharm.com
7 November 2005