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VIDEX Tablets 25mg; VIDEX Tablets 50mg; VIDEX Tablets 100mg
VIDEX Tablets 25mg
VIDEX Tablets 50mg
VIDEX Tablets 100mg
VIDEX Tablets 150mg
VIDEX Paediatric Powder 2g
SCHEDULING STATUS:
S4
PP ZIMBABWE ONLY
2000/7.13/3866
2000/7.13/3867
2000/7.13/3868
2000/7.13/3869
2000/7.13/3870 |
PROPRIETARY NAME
(and dosage form):
VIDEX Tablets 25mg
VIDEX Tablets 50mg
VIDEX Tablets 100mg
VIDEX Tablets 150mg
VIDEX Paediatric Powder 2g
COMPOSITION:
Tablets containing Didanosine (25, 50, 100 and 150mg).
Paediatric powder containing 2g didanosine
PHARMACOLOGICAL CLASSIFICATION:
A20.2.8 Antiviral agents
PHARMACOLOGICAL ACTION:
VIDEX (2',3'-dideoxyinosine or ddI) is an inhibitor of the in vitro replication of the Human Immunodeficiency Virus (HIV) [(also known as HTLV III, LAV)] in human primary cell cultures and in established cell lines. After VIDEX enters the cell, it is enzymatically converted to dideoxyadenosine-triphosphate (ddATP), its active metabolite. In viral nucleic acid replication, incorporation of this 2',3'-dideoxynucleoside prevents chain extension and thereby inhibits viral replication. In addition, ddATP inhibits HIV-reverse transcriptase by competing with dATP for binding to the enzyme's active site, preventing proviral DNA synthesis. The relationship between in vitro susceptibility of HIV to didanosine and clinical response to therapy has not been established. Likewise, in vitro sensitivity results vary greatly and methods to establish virologic responses have not been proven.
PHARMACOKINETICS:
Adults:
Didanosine is rapidly degraded at an acidic pH. Therefore, all oral formulations must contain or be administered with buffering agents designed to increase gastric pH. The presence of food significantly reduces the bioavailability of didanosine. Therefore, VIDEX should be administered at least 30minutes before a meal or 2hours after eating.
Although there is significant variability between patients, Cmax and AUC values increase in proportion to dose. The steady state volume of distribution after IV administration averages 54litres. The concentration of didanosine in the cerebrospinal fluid (CSF), one hour after infusion, averages 21% of that of the simultaneous plasma concentration. Renal clearance in patients with normal renal function which is equivalent to approximately 400mL/min represents an average of 50% of total body clearance, indicating that active tubular secretion, in addition to glomerular filtration is responsible for the renal elimination of didanosine. Urinary recovery of didanosine is approximately 20% of the dose after oral treatment. There is no evidence of didanosine accumulation after the administration of oral doses for 4weeks.
The average elimination half-life is 1,6hours.
The metabolism of didanosine in man has not been eva luated. However, based on animal studies, it is presumed that it follows the same pathways responsible for the elimination of endogenous purines. In vitro human plasma protein binding is less than 5% with didanosine, indicating that drug interactions involving binding site displacement are not anticipated.
Renal impairment: The apparent drug clearance decreased as creatinine clearance decreased. Dose adjustment is recommended in patients with impaired renal function(<60mL/min/1.73m²( see Dosageand Directions for Use)
Hepatic impairment: The metabolism of didanosine may be altered in patients with more severe or other types of hepatic impairment (See Contra-indications)
The AUC of both didanosine and delaviradine are decreased (20%) when administered together. Didanosine also decreases the AUC of indinavir. No clinically significant pharmacokinetic interactions were found between nevirapine, rifabutin, stavudine and zidovudine in specific interaction studies. The effect of rifampicin on the kinetics is not known.
Children:
The average absolute bioavailability at steady state in children is 42%(+18%). Although there is significant variability between patients, Cmax and AUC values increase in proportion to dose in paediatric and adolescent patients. The volume of distribution after IV administration averages 35,6L/m2. The average elimination half-life after oral didanosine administration is 0.8hours. Renal clearance is approximately 243mL/min/m2 after oral dosing and represents about 46% of the total body clearance. Urinary recovery of didanosine is approximately 17% of dose after oral treatment. There is no evidence of didanosine accumulation after oral administration for an average of 26 days. The cerebrospinal fluid didanosine concentration averages 46% (12 to 85%) of the concentration in a simultaneous plasma sample.
INDICATIONS:
VIDEX should be used as part of or in combination with other antiretroviral agents for the palliative treatment of adult and paediatric patients (over 6 months of age) with advanced HIV infection.
This indication is based on increases in CD4 counts observed in patients during therapy with VIDEX. Increases in CD4 counts are considered markers of anti-viral activity and have been linked to clinical benefit in previous AIDS therapy trials
CONTRA-INDICATIONS:
VIDEX is contra-indicated in patients with hypersensitivity to didanosine or any of the components of the formulation.
Safety and efficacy in children under 6months of age has not been established.
There are insufficient data to recommend the use of VIDEX in patients with impaired hepatic function.
Pregnancy and lactation:
Safe use in pregnancy has not been established. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. It is not known whether didanosine is excreted in human milk. It is recommended that women taking didanosine do not breast-feed because of the potential for serious adverse reactions from didanosine in nursing infants.
WARNINGS:
Pancreatitis
Fatal and non-fatal pancreatitis has occurred during therapy with Videx used alone or in combination regimens in both treatment-naïve and treatment-experienced patients, regardless of degree of immunosuppression. Patients treated with Videx in combination with stavudine with or without hydroxyurea may be at increased risk for pancreatitis. Videx should be suspended in patients with signs and symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis.
Suspension should also be considered when biochemical markers of pancreatitis have increased to clinically significant levels even in the absence of symptoms and in patients with clinical symptoms suggestive of pancreatits (eg abdominal pain, nausea, vomiting) until pancreatits is excluded by appropriate laboratory and imaging techniques.
In clinical trials lower rates of pancreatitis were seen in patients with earlier stage HIV infection who were treated with currently recommended doses. The incidence of pancreatitis in clinical trials was dose-related.
When treatment is required with other drugs known to cause pancreatic toxicity (e.g. pentamidine), or known to increase exposure or activity of didanosine (e.g.hydroxyurea or allopurinol) suspension of Videx therapy is recommended. Allopurinol was observed to increase exposure to didanosine in renally impaired patients and healthy volunteers and may increase the risk of dose-related toxicities such as pancreatitis. It is recommended that these two drugs not be administered together (see Precautions, Drug Interactions). Videx should be used with caution in patients with risk factors for pancreatitis. For example the following patients may be at increased risk for developing pancreatitis and should be followed closely for signs and symptoms of pancreatitis; patients with advanced HIV infection, patients with a history of pancreatitis, elderly patients, patients with significantly elevated triglycerides and patients with renal impairment if treated with unadjusted doses.
Patients on didanosine may develop toxic peripheral neuropathy, usually characterised by bilateral symmetrical distal numbness, tingling and pain in feet and hands. Whenever warranted by clinical conditions, didanosine therapy should be suspended until resolution of symptoms. Many patients tolerate a reduced dose after resolution of symptoms.
Liver failure of unknown aetiology has occurred. Patients should be observed for liver enzyme elevations and didanosine should be suspended if enzymes rise to a clinically significant level above the upper limit of normal. In the event of rapidly elevating aminotransferase levels, consideration should be given to discontinuation of all nucleoside analogue therapy (See PRECAUTIONS).
Insufficient clinical experience exists to recommend a dosing regimen in infants under 6months of age.
Paediatric patients have demonstrated retinal or optic nerve changes, particularly at doses above those recommended. There have also been reports of retinal depigmentation and optical neuritis in adults and children. Patients should undergo retinal examination every 6months or if a change in vision occurs. The long-term effects of didanosine are unknown.
VIDEX has been associated with hyperuricaemia. Treatment should be suspended if significant elevations in uric acid levels occur during treatment.
Patients receiving didanosine may continue to develop opportunistic infections and other complications of HIV infection.
DOSAGE AND DIRECTIONS FOR USE:
DUE TO THE REDUCED ABSORPTION IN THE PRESENCE OF FOOD, IT IS RECOMMENDED THAT DIDANOSINE BE ADMINISTERED AT LEAST 30MINUTES BEFORE A MEAL OR 2HOURS AFTER EATING.
Dosage:
Adults:
The recommended starting dose is dependent on weight and may be administered twice daily or once daily. For twice daily dosing the dosing interval should be every 12hours.
ADULT DOSING GUIDELINES
|
Patient Baseline Weight |
VIDEX tablets (*) |
|
>60kg |
200mg 12houly or 400mg once a day |
|
<60kg |
125mg 12houly or 250mg once a day |
Children:
The recommended starting dose is based on body surface area and on a 200mg/m2/day average recommended dose. The recommended dosing interval should be approximately 12hours. The recommended average starting doses are outlined in the table below:
PAEDIATRIC DOSING GUIDELINES
|
Body Surface Area (m2) |
VIDEX Tablets (*) |
|
1,1 - 1,4 |
100 mg 12houly |
|
0,8 - 1,0 |
75mg 12houly |
|
0,5 - 0,7 |
50mg 12houly |
|
<0,4 |
25mg 12houly |
Limited experience with once a day dosing of Videx in paediatric patients suggests similar suppression of HIV replication as seen with twice daily dosing, with a similar safety experience in both treatment groups. Further studies are however needed to eva luate comparative efficacy of the two dosage schedules before the once daily schedule could be adopted as the recommended schedule for paediatric patients.
To ensure that patients taking VIDEX tablets receive a sufficient amount of antacid, each dose must be given as 2 tablets for adults and children older than 1 year, i.e. 2 tablets per day in the once a day schedule or 4 tablets/day on the 12houly schedule. Different strengths of tablets may be combined to yield the recommended dose for example for a 250mg dose one 100mg and one 150mg tablet may be used; for a 200mg dose two 100mg tablets may be used; for a 125mg dose one 100mg and one 25mg tablet may be used; for a 100mg dose two 50mg tablets may be used. Children 6months to 1year should receive a 1-tablet dose, i.e. 2 tablets/day on the 12houly schedule. Safety and efficacy in children under 6months of age have not been established.
Regardless of the dosage used, to avoid potential overdoses of the antacid or phenylalanine component of the tablet formulation no more than 4 tablets should be taken at each dose.
Dose adjustment in patients with renal impairment:
Adults: In adult patients with impaired renal function, the dose of Videx should be adjusted to compensate for the slower rate of elimination. The recommended reductions in dose and/or dosage interval are as follows, based on creatinine clearance.
|
Creatinine clearance (mL/min/1.73m2) |
Patient Weight >60kg Tablets and Non-buffered powder |
Patient Weight <60kg Tablets and Non-buffered powder |
|
>60 (normal dose) |
200mg BID or 400mg QD |
125mg BID or 250mg QD |
|
30 –59 |
100mg BID or 200mg QD |
75mg BID or 150mg QD |
|
10 –29 |
150mg QD |
100mg QD |
|
<10 |
100mg QD |
75mg QD |
For patients undergoing dialysis, the daily dose of Videx should be administered after dialysis. It is not necessary to administer a supplemental dose of Videx following dialysis.
Paediatric patients: Since urinary excretion is also a major route of elimination of didanosine in paediatric patients, the clearance of didanosine may be altered in paediatric patients with renal impairment. Although there are insufficient data to recommend a specific dosage adjustment of Videx in this patient population, a reduction in the dose and/or an increase in the interval between doses should be considered.
Geriatric patients: Because elderly patients are more likely to have decreased renal function care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly.
Patients with symptoms of peripheral neuropathy: If symptoms of peripheralneuropathy occur, Videx therapy should be suspended until resolution of symptoms. After resolution of these symptoms patients may tolerate a reduced dose of Videx.
During treatment with VIDEX, patients should be observed for liver enzyme elevations and VIDEX suspended if enzymes rise to a clinically significant level (See WARNINGS). In the event of rapidly elevating aminotransferase levels, consideration should be given to discontinuation of all nucleoside analogue therapy (See WARNINGS).
When VIDEX is used in combination with other antiretroviral agents, the respective package inserts should be referred to.
Method of preparation. VIDEX chewable/dispersible buffered tablets:
Adults:
Patients should take at least two, but no more than four tablets in each dose, to provide sufficient antacid against acid degradation of didanosine. The tablets should be chewed, or thoroughly dispersed in at least 30mL water prior to consumption.
To disperse tablets, stir until a uniform dispersion forms and drink the entire dispersion immediately. If additional flavouring is desired, the dispersion may be diluted with 30mL of clear apple juice. Stir just prior to consumption. The dispersion with clear apple juice is stable at room temperature not exceeding 25°C for up to one hour.
Children:
Children older than 1 year of age should receive a 2-tablet dose, children 6 months to one year should receive a 1-tablet dose. Tablets should be chewed, or thoroughly dispersed in water prior to consumption as described in the preceding adult-dosing method of preparation. When a one tablet dose is required, the volume of water for dispersion should be 15mL. Fifteen mL of clear apple juice may be added to the dispersion as described above.
VIDEX Paediatric Powder (Non-Buffered)
Prior to dispensing, the dry powder must be reconstituted with purified water to an initial concentration of 20mg/mL and the resulting solution must be mixed immediately with an antacid to a final concentration of 10mg/mL as follows:
For a 20mg/mL initial concentration:
Constitute the product to 20mg/mL by adding 100mL of purified water to the 2g didanosine dry powder, in the product bottle.
For a 10mg/mL final concentration:
|
1. |
Immediately mix 1 part of the 20mg/mL constituted solution with one part of magnesium hydroxide and/or aluminium hydroxide containing antacid suspension, for a final dispensing concentration of 10mg didanosine per mL. |
For patients home use, the constituted-product/antacid mixture should be dispensed in appropriately sized, flint-glass bottles with child-resistant closures. The didanosine solution/antacid mixture is stable for 30days under refrigeration (2-8°C).
Instruct the patient to shake the didanosine/antacid mixture thoroughly prior to use and to store the mixture in a tightly closed container in the refrigerator (2-8°C) up to 30days.
SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects:
Pancreatitis
Fatal and nonfatal pancreatitis has occurred during therapy with Videx used alone or in combination regimens in both treatment-naïve and treatment-experienced patients, regardless of degree of immunosuppression. Videx should be suspended in patients with signs or symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis. Patients treated with Videx in combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitis.
Other important toxicities include lactic acidosis and severe hepatomegaly with steatosis, retinal changes and optical neuritis (See Warnings) and peripheral neuropathy (see Precautions, Dosage and Administration)
When Videx is used in combination with other agents with similar toxicities, the incidences of these toxicities may be higher than when Videx is used alone. Thus patients treated with combination regimens including stavudine may be at increased risk for liver function abnormalities (see Warnings) and peripheral neuropathy (see Precautions)
Patients receiving Videx may develop peripheral neuropathy, usually characterised by bilateral symmetrical distal numbness, tingling and pain in feet, and, less frequently, hands. In clinical trials, the frequency appeared to be related to dose and/or stage of disease. Lower rates were seen in patients with less advanced disease. In controlled clinical trials, neuropathy has occurred more frequently in patients with a history of neuropathy or concomitant use of neurotoxic drug therapy, including stavudine
Some gastrointestinal disturbances may be related to the buffer or antacid component of Videx tablets and prepared powder formulation.
Most of the serious adverse events observed have generally reflected the recognised clinical course of AIDS and AIDS-related complex (ARC). Concurrent dosing with a variety of drugs was allowed in the studies. Therefore, it is difficult to distinguish which events are related to didanosine administration, to the disease itself, or to other therapy-related events.
Diarrhoea, peripheral neurologic symptoms/neuropathy, rash/pruritis, abdominal pain, pancreatitis, nausea, vomiting, headache.
Pancreatitis: Pancreatitis resulting in death was observed in one patient who received didanosine plus stavudine and nelfinavir, one patient who received Videx plus stavudine and indinavir and in 2 of 68patients who received Videx plus stavudine plus indinavir plus hydroxyurea (see Warnings and Precautions, pancreatitis)
Laboratory abnormalities:
Selected laboratory abnormalities in patients receiving didanosine monotherapy and combination therapy in clinical trials are changes in bilirubin, alkaline phosphatase, SGOT, SGPT, GGT, uric acid, lipase and amylase. The relationship to therapy of these observations has not been established. (See Warnings for additional detail about uricemia).
The following events have been identified during post approval use of Videx. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events have been chosen for inclusion due to their seriousness, frequency of reporting or causal connection to didanosine or a combination of these factors:
Body as a whole: alopecia, anaphylactoid reaction, asthenia. Chills/fever and pain.
Digestive disorders: anorexia, dyspepsia and flatulance
Exocrine Gland disorders: pancreatitis (including fatal cases) (see Warnings), sialoadenitis, parotid gland enlargement, dry mouth and dry eyes.
Hematologic Disorders: anemia, granulocytopenia, leukopenia and thrombocytopenia.
Liver: lactic acidosis and hepatic steatosis (see Warnings), hepatitis and liver failure.
Metabolic Disorders: diabetic mellitus, hypoglycemia and hyperglycemia
Musculoskeletal Disorders: myalgia (with or without increases in creatinine phosphokinase),rhabdomyolysis including acute renal failure and hemodialysis, arthralgia and myopathy.
Opthalmologic Disorders: Retinal depigmentation and optic neuritis (see warnings).
Children:
Adverse events and laboratory abnormalities reported to occur in paediatric patients were generally similar to adverse events and laboratory abnormalities reported in adult patients.
In paediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at entry doses below 300mg/m2/day and in 5 of 38 (13%) patients treated at higher doses.
Retinal changes i.e. retinal depigmentation and optic neuritis have been reported in paediatric patients.
The types of laboratory abnormalities in paediatric patients were also similar to those seen in adults. Increases in creatine phosphokinase (>5.1times upper limit of normal ) were reported frequently. The more frequent reported abnormalities in paediatric patients were: Granulocytopenia, SGOT (AST) increased.
Special precautions:
Lactic Acidosis:
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases have been reported with the use of nucleoside analogues alone or in combination, including didanosine and other antiretrovirals. Treatment with VIDEX should be suspended in the setting of rapidly elevating aminotransferase levels, raised blood levels of bilirubin, progressive hepatomegaly, or metabolic/lactic acidosis of unknown aetiology. Caution should be exercised when administering VIDEX to any patient, particularly obese women with hepatomegaly, hepatitis, or other known risk factors for liver disease. These patients should be followed carefully while on therapy with VIDEX.
Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. Didanosine and stavudine are contraindicated in pregnancy (see Contraindications).
Tablet formulation: The magnesium content of each didanosine buffered tablet is 105.95mg. This may represent an excessive load of magnesium in patients with significant renal impairment.
Powder for oral solution: Does not contain sodium. However the sodium contentof antacid products mixed with the didanosine formulation should be considered.
Geriatric use
Elderly patients had a higher frequency of pancreatitis (10%) than younger patients (5%) in an Expanded Access Program that enrolled patients with advanced HIV infection.(See Warnings, Pancreatitis)
Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, renal function should be monitored, and dosage adjustments made accordingly (See Dosage and Administration)
Hyperuricemia:
VIDEX has been associated with asymptomatic hyperuricemia; treatment suspension may be necessary if clinical measures aimed at reducing uric acids levels fail.
Phenylketonurics:
VIDEX tablets contain 36,5mg phenylalanine (from aspartame). Therefore, the use of VIDEX tablets in phenylketonuria patients should be considered only if clearly indicated.
INTERACTIONS:
Specific drug interaction studies have been conducted with ketoconazole, loperamide, metoclopramide, ranitidine, zidovudine, stavudine, rifabutin, foscarnet, trimethoprim, sulfamethoxazole and dapsonewithout evidence of interaction. It is recommended, however, that drugs which can be affected by stomach acidity (e.g. ketoconazole and itraconazole be given at least 2hours prior to dosing with didanosine. Alcohol may exacerbate the toxicity of didanosine. The effect of VIDEX on rifampicin is not known.
Co-administration of didanosine with drugs that are known to cause peripheral neuropathy or pancreatitis may increase the risk of these toxicities. (See WARNINGS
Allopurinol When Videx tablets were coadminstered with allopurinol in 2 patients with renal impairment (creatinine clearance of 15-18mL/min), the AUC of didanosine increased approximately 4-fold. In 14 healthy volunteers, the mean AUC of didanosine increased approximately 2-fold when Videx tablets were given with allopurinol. Thus the risk of dose-related toxicities, such as pancreatitis (see warnings Pancreatitis) may be increased if Videx and allopurinol are administered together. It is recommended that these two drugs not be administered together.
Methadone
When Videx tablets were administered to opiate-dependant patients (n=16) chronically treated with methadone, didanosine exposure as measured by AUC, was decreased by 57%, compared to untreated controls (n=10). If Videx tablets or powder are co-administered with methadone, consideration should be given to increasing the dosage of Videx.
Significant decreases in the AUC’s of delavirdine (20%) and indinavir(84%) occurred following concomitant administration of each of these agents with Videx. To avoid these interactions, these agents should be administered at least one hour prior to dosing Videx. The pharmacokinetics of nelfinavir are not altered to a clinically significant degree when it is administered with a light meal one hour after Videx.
There is no evidence available that didanosine potentiates the myelosuppressive effects of ganciclovir. As with other products containing aluminium antacid components, VIDEX tablets that have been reconstituted with water should not be taken with any tetracycline antibiotic. Likewise, plasma concentrations of some quinolone anti-infective agents eg. ciprofloxacin, may be decreased by administration with antacids contained in VIDEX. Videx tablets or powder formulations should be taken at least 6hours before or 2hours after ciprofloxacin As experience of drug interaction with didanosine is still limited, care should be taken in combining other drug regimens with didanosine.
Ingestion of didanosine with food reduces the amount of didanosine absorbed by as much as 50%.
Failure of dapsone to prevent P. carnii pneumonia in HIV patients has been reported with the concurrent administration of dapsone and didanosine.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
There is no known antidote for didanosine overdosage. Early studies, in which didanosine was initially administered at doses ten times the recommended doses indicate that the anticipated complications of chronic overdosage would be hyperuricaemia, pancreatitis, peripheral neuropathy and hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by haemodialysis. The fractional removal of didanosine during an average haemodialysis session of 3 to 4hours is approximately 20-35% of the amount present in the body at the start of dialysis.
IDENTIFICATION:
VIDEX tablets are off-white to light orange/yellow mottled, round, flat-faced tablets embossed with "VIDEX BMS" on one side and the strength on the other.
VIDEX Paediatric powder is a white to off-white powder.
PRESENTATION:
VIDEX Tablets:
High density polyethylene bottle with child-resistant cap (60 tablets per bottle).
VIDEX Paediatric Powder:
Glass bottle with 2g powder for reconstitution.
STORAGE INSTRUCTIONS:
VIDEX tablets should be stored in tightly closed bottles at room temperature not exceeding 25°C. If dispersed in water, the dose may be held for up to one hour at ambient temperature.
VIDEX Paediatric powder: The bottles with the dry product should be stored at room temperature not exceeding 25°C. The constituted VIDEX solution/antacid mixture may be stored up to 30days in a refrigerator (2-8°C). Discard any unused portion after 30days.
REGISTRATION NUMBERS:
VIDEX Tablets 25mg: 27/20.2.8/40
VIDEX Tablets 50mg: 27/20.2.8/41
VIDEX Tablets 100mg: 27/20.2.8/42
VIDEX Tablets 150mg: 27/20.2.8/43
VIDEX Paediatric Powder 2g: 27/20.2.8/0045
NAME AND BUSINESS ADDRESS OF APPLICANT:
Bristol-Myers Squibb (Pty) Ltd*
47 Van Buuren Road
BEDFORDVIEW
2008
DATE OF PUBLICATION OF THIS PACKAGE INSERT:
July 2002
*Authorised user of the TM VIDEX
Updated on this site: January 2003
Current: June 2005
Source: Pharmaceutical Industry |
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