Renagel 800 mg film-coated tablets

1. Name Of The Medicinal Product

Renagel 800 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each tablet contains 800 mg sevelamer hydrochloride.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet (tablet)

The off-white, oval tablets are imprinted with “Renagel 800” on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Renagel is indicated for the control of hyperphosphataemia in adult patients receiving haemodialysis or peritoneal dialysis. Renagel should be used within the context of a multiple therapeutic approach, which could include calcium supplements, 1,25 – dihydroxy Vitamin D₃ or one of its analogues to control the development of renal bone disease.

4.2 Posology And Method Of Administration

Posology

Starting dose

The recommended starting dose of Renagel is 2.4 g or 4.8 g per day based on clinical needs and serum phosphorus level. Renagel must be taken three times per day with meals.

Serum phosphate level in patients not on phosphate binders	Starting dose of Renagel 800 mg tablets
1.76 – 2.42 mmol/l (5.5-7.5 mg/dl)	1 tablet, 3 times per day
> 2.42 mmol/l (>7.5 mg/dl)	2 tablets, 3 times per day

For patients previously on phosphate binders, Renagel should be given on a gram for gram basis with monitoring of serum phosphorus levels to ensure optimal daily doses.

Titration and maintenance

Serum phosphate levels should be closely monitored and the dose of Renagel adjusted accordingly with the goal of lowering serum phosphate to 1.76 mmol/l (5.5 mg/dl) or less. Serum phosphate should be tested every two to three weeks until a stable serum phosphate level is reached and on a regular basis thereafter.

The dose range may vary between 1 and 5 tablets of 800 mg per meal. The average actual daily dose used in the chronic phase of a one year clinical study was 7 grams of sevelamer.

Paediatric population

The safety and efficacy of this product has not been established in patients below the age of 18 years. Renagel is not recommended in children below the age of 18 years.

Renal impairment

The safety and efficacy of this product has not been established in predialysis patients. Renagel is not recommended in these patients.

Method of administration

For oral use

Patients should take Renagel with meals and adhere to their prescribed diets. The tablets must be swallowed whole. Do not chew.

4.3 Contraindications

• Hypersensitivity to sevelamer or to any of the excipients..

• Hypophosphataemia

• Bowel obstruction.

4.4 Special Warnings And Precautions For Use

Efficacy and safety of Renagel has not been studied in patients with:

• swallowing disorders

• active inflammatory bowel disease

• gastrointestinal motility disorders including untreated or severe gastroparesis, diverticulosis, retention of gastric contents and abnormal or irregular bowel motion

• patients with a history of major gastrointestinal surgery

Therefore caution should be exercised when Renagel is used in patients with these disorders.

Intestinal obstruction and ileus/subileus

In very rare cases, intestinal obstruction and ileus/subileus have been observed in patients during treatment with Renagel. Constipation may be a preceding symptom. Patients who are constipated should be monitored carefully while being treated with Renagel. Renagel treatment should be re-evaluated in patients who develop severe constipation or other severe gastrointestinal symptoms.

Fat-soluble vitamins

Depending on diet intake and the nature of end stage renal failure, dialysis patients may develop low vitamin A, D, E and K levels. It cannot be excluded that Renagel can bind fat

Folate deficiency

There is at present insufficient data to exclude the possibility of folate deficiency during long term Renagel treatment.

Hypocalcaemia/hypercalcaemia

Patients with renal insufficiency may develop hypocalcaemia or hypercalcaemia. Renagel does not contain calcium. Serum calcium levels should be monitored as is done in normal follow-up of a dialysis patient. Elemental calcium should be given as a supplement in case of hypocalcaemia.

Metabolic acidosis

Patients with chronic renal failure are predisposed to developing metabolic acidosis. Worsening of acidosis has been reported upon switching from other phosphate binders to sevelamer in a number of studies where lower bicarbonate levels in the sevelamer-treated patients compared to patients treated with calcium-based binders were observed. Closer monitoring of serum bicarbonate levels is therefore recommended.

Peritonitis

Patients receiving dialysis are subject to certain risks for infection specific to the dialysis modality. Peritonitis is a known complication in patients receiving peritoneal dialysis (PD) and in a clinical study with Renagel, a number of peritonitis cases were reported. Therefore, patients on PD should be closely monitored to ensure the reliable use of appropriate aseptic technique with the prompt recognition and management of any signs and symptoms associated with peritonitis.

Anti-arrhythmic and anti-seizure medicinal products

Caution should be exercised when prescribing Renagel to patients also taking anti

Hypothyroidism

Closer monitoring of patients with hypothyroidism co-administered with sevelamer hydrochloride and levothryroxine is recommended (see section 4.5).

Long term chronic treatment

As data on the chronic use of sevelamer for over one year are not yet available, potential absorption and accumulation of sevelamer during long-term chronic treatment cannot be totally excluded (see section 5.2 Pharmacokinetics).

Hyperparathyroidism

Renagel alone is not indicated for the control of hyperparathyroidism. In patients with secondary hyperparathyroidism Renagel should be used within the context of a multiple therapeutic approach, which could include calcium supplements, 1,25 - dihydroxy Vitamin D₃ or one of its analogues to lower the intact parathyroid hormone (iPTH) levels.

Serum chloride

Serum chloride may increase during Renagel treatment as chloride may be exchanged for phosphorus in the intestinal lumen. Although no clinically significant serum chloride increase has been observed in the clinical studies, serum chloride should be monitored as is done in the routine follow-up of a dialysis patient. One gram of Renagel contains approximately 180 mg (5.1mEq) chloride.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have not been conducted in patients on dialysis.

In interaction studies in healthy volunteers, Renagel decreased the bioavailability of ciprofloxacin by approximately 50% when co-administered with Renagel in a single dose study. Consequently, Renagel should not be taken simultaneously with ciprofloxacin.

Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from clinical trials. Caution should be exercised when prescribing Renagel to patients also taking these medications.

During post marketing experience, very rare cases of increased TSH levels have been reported in patients co-administered Renagel and levothyroxine. Closer monitoring of TSH levels is therefore recommended in patients receiving both medications.

Reduced levels of ciclosporin, mycophenolate mofetil and tacrolimus have been reported in transplant patients when coadministered with Renagel without any clinical consequences (i.e graft rejection). The possibility of an interaction cannot be excluded and a close monitoring of blood concentrations of mycophenolate mofetil, ciclosporin and tacrolimus should be considered during the use of combination and after its withdrawal.

In interaction studies in healthy volunteers, Renagel had no effect on the bioavailability of digoxin, warfarin, enalapril or metoprolol.

Renagel is not absorbed and may affect the bioavailability of other medicinal products. When administering any medicinal product where a reduction in the bioavailability could have a clinically significant effect on safety or efficacy, the medicinal product should be administered at least one hour before or three hours after Renagel, or the physician should consider monitoring blood levels.

4.6 Pregnancy And Lactation

Pregnancy:

The safety of Renagel has not been established in pregnant women. In animal studies there was no evidence that sevelamer induced embryo-foetal toxicity. Renagel should only be given to pregnant women if clearly needed and after a careful risk/benefit analysis has been conducted for both the mother and the foetus (See 5.3 Preclinical safety data).

Lactation:

The safety of Renagel has not been established in lactating women. Renagel should only be given to lactating women if clearly needed and after a careful risk/benefit analysis has been conducted for both the mother and the infant (See 5.3 Preclinical safety data).

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on ability to drive and use machines have been performed.

4.8 Undesirable Effects

In parallel design studies involving 244 haemodialysis patients with treatment duration of up to 54 weeks and 97 peritoneal dialysis patients with treatment duration of 12 weeks, the most frequently occurring (

Gastrointestinal disorders

Very common (

Common (

Post-marketing experience: During post-approval use of Renagel, cases of pruritus, rash, abdominal pain, intestinal obstruction, ileus/subileus, diverticulitis and intestinal perforation have been reported.

4.9 Overdose

No case of overdose has been reported.

Renagel has been given to normal healthy volunteers in doses up to 14 grams, the equivalent of seventeen 800 mg tablets, per day for eight days with no undesirable effects.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Treatment of hyperphosphatemia. ATC code: V03AE02.

Renagel contains sevelamer, a non-absorbed phosphate binding poly(allylamine hydrochloride) polymer, free of metal and calcium. It contains multiple amines separated by one carbon from the polymer backbone. These amines become partially protonated in the intestine and interact with phosphate molecules through ionic and hydrogen bonding. By binding phosphate in the gastrointestinal tract, sevelamer lowers the phosphate concentration in the serum.

In clinical trials, selevamer has been shown to be effective in reducing serum phosphorus in patients receiving haemodialysis or peritoneal dialysis.

Sevelamer decreases the incidence of hypercalcaemic episodes as compared to patients using calcium based phosphate binders alone, probably because the product itself does not contain calcium. The effects on phosphate and calcium were proven to be maintained throughout a study with one year follow-up.

Sevelamer has been shown to bind bile acids in vitro and in vivo in experimental animal models. Bile acid binding by ion exchange resins is a well-established method of lowering blood cholesterol. In clinical trials mean total and LDL cholesterol declined by 15-31%. This effect is observed after 2 weeks is maintained with long-term treatment. Triglycerides, HDL cholesterol and albumin did not change.

In the clinical studies in haemodialysis patients, sevelamer alone did not have a consistent and clinically significant effect on serum intact parathyroid hormone (iPTH). In the 12 week study involving peritoneal dialysis patients however, similar iPTH reductions were seen compared with patients receiving calcium acetate. In patients with secondary hyperparathyroidism Renagel should be used within the context of a multiple therapeutic approach, which could include calcium supplements, 1,25 – dihydroxy Vitamin D₃ or one of its analogues to lower the intact parathyroid hormone (iPTH) levels.

In a clinical trial of one-year duration, Renagel had no adverse effect on bone turnover or mineralisation compared to calcium carbonate.

5.2 Pharmacokinetic Properties

Renagel is not absorbed from the gastrointestinal tract according to a single dose pharmacokinetic study in healthy volunteers. Pharmacokinetic studies have not been carried out in renal failure patients (see section 4.4 Special warnings and special precautions for use).

5.3 Preclinical Safety Data

In preclinical studies in rats and dogs, Renagel at a dose of 10 times the maximum human doses reduced absorption of fat soluble vitamins D, E and K, and folic acid.

In a study in rats, administering sevelamer in 15-30 x the human dose, an increase in serum copper was detected. This was not confirmed in a dog study or in clinical trials.

Currently, no formal carcinogenicity data are available. However, in vitro and in vivo studies have indicated that Renagel does not have genotoxic potential. Also the medicinal product is not absorbed in the gastrointestinal tract.

In reproduction studies there was no evidence that sevelamer induced embryolethality, foetotoxicity or teratogenicity at the doses tested (up to 1 g/kg/day in rabbits and up to 4.5 g/kg/day in rats). Deficits in skeletal ossification were observed in several locations in fetuses of female rats dosed with sevelamer at 8-20 times the maximum human dose of 200 mg/kg. The effects may be secondary to vitamin D and/or vitamin K depletion at these high doses.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

Silica, colloidal anhydrous

Stearic acid

Film-coating:

Hypromellose

Diacetylated monoglycerides

Printing ink:

Iron oxide black (E172)

Propylene glycol

Hypromellose

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above25ºC.

Keep the bottle tightly closed in order to protect from moisture.

6.5 Nature And Contents Of Container

HDPE bottles, with a child resistant polypropylene cap and a foil induction seal.

Package sizes are:

6 bottles of 30 tablets

1bottle of 100 tablets

1 bottle of 180 tablets

2 bottles of 180 tablets

3 bottles of 180 tablets

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Genzyme Europe B.V., Gooimeer 10, 1411 DD Naarden, The Netherlands

8. Marketing Authorisation Number(S)

EU/1/99/123/008

EU/1/99/123/009

EU/1/99/123/010

EU/1/99/123/011

EU/1/99/123/012

EU/1/99/123/013

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 28/01/2000

Renewal date: 02/02/2010

10. Date Of Revision Of The Text

06/2010

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.

Boots Antifungal Cream

Boots Antifungal Cream

(Clotrimazole)

for fungal infections of the skin

20 g

Read all of this carton for full instructions.

What this medicine is for

An antifungal cream for the treatment of fungal skin infections including ringworm, athlete’s foot, fungal nappy rash, infections of the armpit, groin, toes and skin folds and thrush of the vulva or penis.

Before you use this medicine

Do not use:

• 
  If you are allergic to any of the ingredients


• 
  If you are pregnant or breastfeeding, unless your doctor or midwife tells you to

Information about some of the ingredients: The ingredients in the cream may affect the latex used in contraceptives such as condoms and diaphragms. This may reduce the effectiveness of the contraceptives. You should therefore use other methods of contraception for at least 5 days after using this medicine in the genital area. You may, for example, use a spermicide gel in addition to the condom or diaphragm. If you need more advice about this speak to your pharmacist.

Cetyl alcohol and stearyl alcohol in this medicine may cause skin reactions (e.g. contact dermatitis).

How to use this medicine

Check the tube seal is not broken before first use. If it is, do not use the cream.

Pierce tube seal with end of cap.

Adults and children: Apply to the affected area two or three times a day. Use the cream for at least 2 weeks. In some cases it may be necessary to continue to use the cream for more than 4 weeks.

If you are using the cream for a foot infection, make sure your feet, especially between the toes, are washed and thoroughly dried before applying the cream. Apply to the skin only.

Do not use more than the amount recommended above.

If symptoms do not go away talk to your doctor.

If anyone accidentally swallows some: Talk to a doctor straight away.

Possible side effects

Most people will not have problems, but some may get some.

If you get these side effects, stop using the cream and see a doctor:

• Allergic reaction (e.g. skin rash, red or itchy skin)

These other effects are less serious. If they bother you talk to a pharmacist:

• Rarely, mild burning or irritation immediately after using the cream


• Pain

If any side effect becomes severe, or you notice any side effect not listed here, please tell your pharmacist or doctor.

Keep all medicines out of the sight and reach of children.

Use by the date on the end flap of the carton.

Active ingredient

This topical cream contains Clotrimazole 1% w/w.

Also contains: purified water, 2-octyldodecanol, stearyl alcohol, cetyl alcohol, cetyl esters wax, sorbitan stearate, polysorbate 60, benzyl alcohol.

PL 10622/0004 [P]

Text prepared 8/08

Manufactured for

The Boots Company PLC

Nottingham

NG2 3AA

by

Thornton & Ross Ltd

Linthwaite

Huddersfield

West Yorkshire

HD7 5QH

Marketing Authorisation held by

PLIVA Pharma Ltd

Vision House

Bedford Road

Petersfield

Hampshire

GU32 2QB

If you need more advice ask your pharmacist.

1498cXPil

Emozul 40 mg gastro-resistant capsules, hard

1. Name Of The Medicinal Product

Emozul^® 40 mg gastro-resistant capsules, hard

2. Qualitative And Quantitative Composition

Each gastro-resistant capsule, hard, contains 40 mg esomeprazole (as esomeprazole magnesium dihydrate).

Excipient:

sucrose

56.93–65.11 mg

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Gastro-resistant capsule, hard.

The body and the cap are off-pink in colour; the capsules contain white to almost white pellets.

4. Clinical Particulars

4.1 Therapeutic Indications

Emozul capsules are indicated for:

Gastroesophageal Reflux Disease (GORD)

- treatment of erosive reflux oesophagitis

- long-term management of patients with healed oesophagitis to prevent relapse

- symptomatic treatment of gastroesophageal reflux disease (GORD)

In combination with appropriate antibacterial therapeutic regimens for the eradication of Helicobacter pylori and

- healing of Helicobacter pylori associated duodenal ulcer and

- prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcers

Patients requiring continued NSAID therapy

Healing of gastric ulcers associated with NSAID therapy.

Prevention of gastric and duodenal ulcers associated with NSAID therapy, in patients at risk.

Prolonged treatment after IV induced prevention of rebleeding of peptic ulcers.

Treatment of Zollinger Ellison Syndrome

4.2 Posology And Method Of Administration

The capsules should be swallowed whole with some water. The capsules should not be chewed or crushed.

For patients who have difficulty in swallowing, the capsules can also be opened and the pellets mixed in half a glass of non-carbonated water. No other liquids should be used as the enteric coating may be dissolved. Drink the water with the pellets immediately or within 30 minutes. Rinse the glass with half a glass of water and drink. The pellets must not be chewed or crushed.

For patients who cannot swallow, the capsules can be opened and pellets mixed in non-carbonated water and administered through a gastric tube. It is important that the appropriateness of the selected syringe and tube is carefully tested before use (see section 6.6).

Adults and adolescents from the age of 12 years

Gastroesophageal Reflux Disease (GORD)

- treatment of erosive reflux oesophagitis

40 mg once daily for 4 weeks.

An additional 4 weeks treatment is recommended for patients in whom oesophagitis has not healed or who have persistent symptoms.

- long-term management of patients with healed oesophagitis to prevent relapse

20 mg once daily.

- symptomatic treatment of gastroesophageal reflux disease (GORD)

20 mg once daily in patients without oesophagitis. If symptom control has not been achieved after 4 weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using 20 mg once daily. In adults, an on demand regimen taking 20 mg once daily, when needed, can be used. In NSAID treated patients at risk of developing gastric and duodenal ulcers, subsequent symptom control using an on demand regimen is not recommended.

Adults

In combination with appropriate antibacterial therapeutic regimens for the eradication of Helicobacter pylori and

- healing of Helicobacter pylori associated duodenal ulcer and

- prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcers.

20 mg Emozul with 1 g amoxicillin and 500 mg clarithromycin, all twice daily for 7 days.

Patients requiring continued NSAID therapy

Healing of gastric ulcers associated with NSAID therapy: The usual dose is 20 mg once daily. The treatment duration is 4-8 weeks.

Prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk: 20 mg once daily.

Prolonged treatment after IV induced prevention of rebleeding of peptic ulcers

40 mg once daily for 4 weeks after IV induced prevention of rebleeding of peptic ulcers.

Treatment of Zollinger Ellison Syndrome

The recommended initial dosage is Emozul 40 mg twice daily. The dosage should then be individually adjusted and treatment continued as long as clinically indicated. Based on the clinical data available, the majority of patients can be controlled on doses between 80 to 160 mg esomeprazole daily. With doses above 80 mg daily, the dose should be divided and given twice daily.

Children below the age of 12 years

Emozul should not be used in children younger than 12 years since no data is available.

Impaired renal function

Dose adjustment is not required in patients with impaired renal function. Due to limited experience in patients with severe renal insufficiency, such patients should be treated with caution (see section 5.2).

Impaired hepatic function

Dose adjustment is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, a maximum dose of 20 mg Emozul should not be exceeded (see section 5.2).

Elderly

Dose adjustment is not required in the elderly.

Do not eat the desiccant capsule provided in the container.

4.3 Contraindications

Known hypersensitivity to esomeprazole, substituted benzimidazoles or any of the excipients.

Esomeprazole should not be used concomitantly with nelfinavir (see section 4.5).

4.4 Special Warnings And Precautions For Use

In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with Emozul may alleviate symptoms and delay diagnosis.

Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance.

Patients on on-demand treatment should be instructed to contact their physician if their symptoms change in character. When prescribing esomeprazole for on demand therapy, the implications for interactions with other pharmaceuticals, due to fluctuating plasma concentrations of esomeprazole should be considered (see section 4.5).

When prescribing esomeprazole for eradication of Helicobacter pylori possible active substance interactions for all components in the triple therapy should be considered. Clarithromycin is a potent inhibitor of CYP3A4 and hence contraindications and interactions for clarithromycin should be considered when the triple therapy is used in patients concurrently taking other medicinal products metabolised via CYP3A4 such as cisapride.

Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter (see section 5.1).

Co-administration of esomeprazole with atazanavir is not recommended (see section 4.5). If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg of ritonavir; esomeprazole 20 mg should not be exceeded.

Special information about some of the ingredients

Emozul contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effects of esomeprazole on the pharmacokinetics of other active substances

Medicinal products with pH dependent absorption

The decreased intragastric acidity during treatment with esomeprazole, might increase or decrease the absorption of active substances if the mechanism of absorption is influenced by gastric acidity. In common with the use of other inhibitors of acid secretion or antacids, the absorption of ketoconazole and itraconazole can decrease during treatment with esomeprazole.

Omeprazole has been reported to interact with some protease inhibitors. The clinical importance and the mechanisms behind these reported interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the protease inhibitors. Other possible interaction mechanisms are via inhibition of CYP 2C19. For atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole and concomitant administration is not recommended. Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a substantial reduction in atazanavir exposure (approximately 75% decrease in AUC, C_max and C_min). Increasing the atazanavir dose to 400 mg did not compensate for the impact of omeprazole on atazanavir exposure. The co-administration of omeprazole (20 mg once daily) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease of approximately 30% in the atazanavir exposure as compared with the exposure observed with atazanavir 300 mg/ritonavir 100 mg once daily without omeprazole 20 mg once daily. Co-administration of omeprazole (40 mg once daily) reduced mean nelfinavir AUC, C_max and C_min by 36-39 % and mean AUC, C_max and C_min for the pharmacologically active metabolite M8 was reduced by 75-92%. For saquinavir (with concomitant ritonavir), increased serum levels (80-100%) have been reported during concomitant omeprazole treatment (40 mg once daily). Treatment with omeprazole 20 mg once daily had no effect on the exposure of darunavir (with concomitant ritonavir) and amprenavir (with concomitant ritonavir). Treatment with esomeprazole 20 mg once daily had no effect on the exposure of amprenavir (with and without concomitant ritonavir). Treatment with omeprazole 40 mg once daily had no effect on the exposure of lopinavir (with concomitant ritonavir). Due to the similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, concomitant administration with esomeprazole and atazanavir is not recommended and concomitant administration with esomeprazole and nelfinavir is contraindicated.

Active substances metabolised by CYP2C19

Esomeprazole inhibits CYP2C19, the major esomeprazole metabolising enzyme. Thus, when esomeprazole is combined with active substances metabolised by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin etc., the plasma concentrations of these active substances may be increased and a dose reduction could be needed. This should be considered especially when prescribing esomeprazole for on demand therapy. Concomitant administration of 30 mg esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam. Concomitant administration of 40 mg esomeprazole resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients. It is recommended to monitor the plasma concentrations of phenytoin when treatment with esomeprazole is introduced or withdrawn. Omeprazole (40 mg once daily) increased voriconazole (a CYP2C19 substrate) C_max and AUC by 15% and 41%, respectively.

Concomitant administration of 40 mg esomeprazole to warfarin-treated patients in a clinical trial showed that coagulation times were within the accepted range. However, post-marketing, a few isolated cases of elevated INR of clinical significance have been reported during concomitant treatment. Monitoring is recommended when initiating and ending concomitant esomeprazole treatment during treatment with warfarin or other coumarine derivatives.

In healthy volunteers, concomitant administration of 40 mg esomeprazole resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life (t_½) but no significant increase in peak plasma levels of cisapride. The slightly prolonged QTc interval observed after administration of cisapride alone, was not further prolonged when cisapride was given in combination with esomeprazole (see also section 4.4).

Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin or quinidine.

Studies evaluating concomitant administration of esomeprazole and either naproxen or rofecoxib did not identify any clinically relevant pharmacokinetic interactions during short-term studies.

Effects of other active substances on the pharmacokinetics of esomeprazole

Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant administration of esomeprazole and a CYP3A4 inhibitor, clarithromycin (500 mg b.i.d.), resulted in a doubling of the exposure (AUC) to esomeprazole. Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP 3A4 may result in more than doubling of the esomeprazole exposure. The CYP2C19 and CYP3A4 inhibitor voriconazole increased omeprazole AUC by 280%. A dose adjustment of esomeprazole is not regularly required in either of these situations. However, dose adjustment should be considered in patients with severe hepatic impairment and if long-term treatment is indicated.

4.6 Pregnancy And Lactation

For esomeprazole, clinical data on exposed pregnancies are insufficient. With the racemic mixture, omeprazole, data on a larger number of exposed pregnancies from epidemiological studies indicate no malformative nor foetotoxic effect. Animal studies with esomeprazole do not indicate direct or indirect harmful effects with respect to embryonal/fetal development. Animal studies with the racemic mixture do not indicate direct or indirect harmful effects with respect to pregnancy, parturition or postnatal development. Caution should be exercised when prescribing to pregnant women.

It is not known whether esomeprazole is excreted in human breast milk. No studies in lactating women have been performed. Therefore Emozul should not be used during breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

Emozul has no influence on the ability to drive and use machines.

4.8 Undesirable Effects

The following adverse drug reactions have been identified or suspected in the clinical trials programme for esomeprazole and post-marketing. None was found to be dose-related.

The reactions are classified according to frequency:

- Very common (

- Common (

- Uncommon (

- Rare (

- Very rare (<1/10,000)

- Not known (cannot be estimated from the available data)

Blood and lymphatic system disorders

Rare: Leukopenia, thrombocytopenia

Very rare: Agranulocytosis, pancytopenia

Immune system disorders

Rare: Hypersensitivity reactions e.g. fever, angioedema and anaphylactic reaction/shock

Metabolism and nutrition disorders

Uncommon: Peripheral oedema

Rare: Hyponatraemia

Psychiatric disorders

Uncommon: Insomnia

Rare: Agitation, confusion, depression

Very rare: Aggression, hallucinations

Nervous system disorders

Common: Headache

Uncommon: Dizziness, paraesthesia, somnolence

Rare: Taste disturbance

Eye disorders

Rare: Blurred vision

Ear and labyrinth disorders

Uncommon: Vertigo

Respiratory, thoracic and mediastinal disorders

Rare: Bronchospasm

Gastrointestinal disorders

Common: Abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting

Uncommon: Dry mouth

Rare: Stomatitis, gastrointestinal candidiasis

Hepatobiliary disorders

Uncommon: Increased liver enzymes

Rare: Hepatitis with or without jaundice

Very rare: Hepatic failure, encephalopathy in patients with pre-existing liver disease

Skin and subcutaneous tissue disorders

Uncommon: Dermatitis, pruritus, rash, urticaria

Rare: Alopecia, photosensitivity

Very rare: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN)

Musculoskeletal, connective tissue and bone disorders

Rare: Arthralgia, myalgia

Very rare: Muscular weakness

Renal and urinary disorders

Very rare: Interstitial nephritis

Reproductive system and breast disorders

Very rare: Gynaecomastia

General disorders and administration site conditions

Rare: Malaise, increased sweating

4.9 Overdose

There is very limited experience to date with deliberate overdose. The symptoms described in connection with 280 mg were gastrointestinal symptoms and weakness. Single doses of 80 mg esomeprazole were uneventful. No specific antidote is known. Esomeprazole is extensively plasma protein bound and is therefore not readily dialyzable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: proton pump inhibitors

ATC Code: A02B C05

Esomeprazole is the S-isomer of omeprazole and reduces gastric acid secretion through a specific targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. Both the R- and S-isomer of omeprazole have similar pharmacodynamic activity.

Site and mechanism of action

Esomeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the secretory canaliculi of the parietal cell, where it inhibits the enzyme H⁺K⁺-ATPase – the acid pump and inhibits both basal and stimulated acid secretion.

Effect on gastric acid secretion

After oral dosing with esomeprazole 20 mg and 40 mg the onset of effect occurs within one hour. After repeated administration with 20 mg esomeprazole once daily for five days, mean peak acid output after pentagastrin stimulation is decreased 90% when measured 6-7 hours after dosing on day five.

After five days of oral dosing with 20 mg and 40 mg of esomeprazole, intragastric pH above 4 was maintained for a mean time of 13 hours and 17 hours, respectively over 24 hours in symptomatic GORD patients. The proportion of patients maintaining an intragastric pH above 4 for at least 8, 12 and 16 hours respectively were for esomeprazole 20 mg 76%, 54% and 24%. Corresponding proportions for esomeprazole 40 mg were 97%, 92% and 56%.

Using AUC as a surrogate parameter for plasma concentration, a relationship between inhibition of acid secretion and exposure has been shown.

Therapeutic effects of acid inhibition

Healing of reflux oesophagitis with esomeprazole 40 mg occurs in approximately 78% of patients after four weeks, and in 93% after eight weeks.

One week treatment with esomeprazole 20 mg b.i.d. and appropriate antibiotics, results in successful eradication of H. pylori in approximately 90% of patients.

After eradication treatment for one week there is no need for subsequent monotherapy with antisecretory active substances for effective ulcer healing and symptom resolution in uncomplicated duodenal ulcers.

In a randomized, double blind, placebo-controlled clinical study, patients with endoscopically confirmed peptic ulcer bleeding characterised as Forrest Ia, Ib, IIa or IIb (9%, 43%, 38% and 10% respectively) were randomized to receive esomeprazole solution for infusion (n=375) or placebo (n=389). Following endoscopic hemostasis, patients received either 80 mg esomeprazole as an intravenous infusion over 30 minutes followed by a continuous infusion of 8 mg per hour or placebo for 72 hours. After the initial 72 hour period, all patients received open-label 40 mg oral esomeprazole for 27 days for acid suppression The occurrence of rebleeding within 3 days was 5.9% in the esomeprazole treated group compared to 10.3% for the placebo group. At 30 days post-treatment, the occurrence of rebleeding in the esomeprazole treated versus the placebo treated group 7.7% vs 13.6%.

Other effects related to acid inhibition

During treatment with antisecretory active substances serum gastrin increases in response to the decreased acid secretion.

An increased number of ECL cells (enterochromaffin-like cells), possibly related to the increased serum gastrin levels, have been observed in some patients during long term treatment with esomeprazole.

During long-term treatment with antisecretory active substances gastric glandular cysts have been reported to occur at a somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible.

Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter.

In two studies with ranitidine as an active comparator, esomeprazole showed better effect in healing of gastric ulcers in patients using NSAIDs, including COX-2 selective NSAIDs.

In two studies with placebo as comparator, esomeprazole showed better effect in the prevention of gastric and duodenal ulcers in patients using NSAIDs (aged >60 and/or with previous ulcer), including COX-2 selective NSAIDs.

5.2 Pharmacokinetic Properties

Absorption and distribution

Esomeprazole is acid labile and is administered orally as enteric-coated granules. In vivo conversion to the R-isomer is negligible. Absorption of esomeprazole is rapid, with peak plasma levels occurring approximately 1-2 hours after dose. The absolute bioavailability is 64% after a single dose of 40 mg and increases to 89% after repeated once-daily administration. For 20 mg esomeprazole the corresponding values are 50% and 68% respectively.The apparent volume of distribution at steady state in healthy subjects is approximately 0.22 l/kg body weight. Esomeprazole is 97% plasma protein bound.

Food intake both delays and decreases the absorption of esomeprazole although this has no significant influence on the effect of esomeprazole on intragastric acidity.

Metabolism and excretion

Esomeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxy- and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma.

The parameters below reflect mainly the pharmacokinetics in individuals with a functional CYP2C19 enzyme, extensive metabolisers.

Total plasma clearance is about 17 l/h after a single dose and about 9 l/h after repeated administration. The plasma elimination half-life is about 1.3 hours after repeated once-daily dosing. The pharmacokinetics of esomeprazole has been studied in doses up to 40 mg b.i.d. The area under the plasma concentration-time curve increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a more than dose proportional increase in AUC after repeated administration. This time - and dose-dependency is due to a decrease of first pass metabolism and systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulphone metabolite. Esomeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once-daily administration.

The major metabolites of esomeprazole have no effect on gastric acid secretion. Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the faeces. Less than 1% of the parent compound is found in urine.

Special patient populations

Approximately 2.9 ± 1.5% of the population lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals the metabolism of esomeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were increased by about 60%.

These findings have no implications for the posology of esomeprazole.

The metabolism of esomeprazole is not significantly changed in elderly subjects (71-80 years of age).

Following a single dose of 40 mg esomeprazole the mean area under the plasma concentration-time curve is approximately 30% higher in females than in males. No gender difference is seen after repeated once-daily administration. These findings have no implications for the posology of esomeprazole.

Impaired organ function

The metabolism of esomeprazole in patients with mild to moderate liver dysfunction may be impaired. The metabolic rate is decreased in patients with severe liver dysfunction resulting in a doubling of the area under the plasma concentration-time curve of esomeprazole. Therefore, a maximum of 20 mg should not be exceeded in patients with severe dysfunction. Esomeprazole or its major metabolites do not show any tendency to accumulate with once-daily dosing.

No studies have been performed in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function.

Paediatric

Adolescents 12-18 years:

Following repeated dose administration of 20 mg and 40 mg esomeprazole, the total exposure (AUC) and the time to reach maximum plasma concentration (t_max) in 12 to18 year-olds was similar to that in adults for both esomeprazole doses.

5.3 Preclinical Safety Data

Preclinical bridging studies reveal no particular hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction. Carcinogenicity studies in the rat with the racemic mixture have shown gastric ECL-cell hyperplasia and carcinoids. These gastric effects in the rat are the result of sustained, pronounced hypergastrinaemia secondary to reduced production of gastric acid and are observed after long-term treatment in the rat with inhibitors of gastric acid secretion.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Pellets in the capsule core:

Sugar spheres (sucrose and maize starch)

Povidone K30

Sodium laurilsulfate

Poly(vinyl alcohol)

Titanium dioxide (E171)

Macrogol

Talc (E553b)

Magnesium carbonate, heavy

Polysorbate 80 (E433)

Methacrylic acid – ethyl acrylate copolymer (1:1) dispersion 30 per cent

Capsule shell:

Gelatin (E441)

Titanium dioxide (E171)

Red iron oxide (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Blister pack/HDPE container: 24 months.

HDPE container: after first opening, the product should be used within 6 months.

6.4 Special Precautions For Storage

This medicinal product does not require any special temperature storage conditions.

Blister pack

Store in the original package in order to protect from moisture.

HDPE container

Keep the container tightly closed in order to protect from moisture.

6.5 Nature And Contents Of Container

Blister packs consisting of cold formed OPA/Al/PE + DES film and aluminium foil: 7, 10, 14, 15, 28, 30, 50, 56, 60, 90, 98 and 100 gastro-resistant capsules, hard, in a box.

HDPE container, PP closure with a desiccant: 98 gastro-resistant capsules, hard, and a desiccant capsule, in a box. Do not eat the desiccant capsule provided in the container.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Any unused product or waste material should be disposed of in accordance with local requirements.

Administration through gastric tube

1. Open the capsule and empty the pellets into an appropriate syringe and fill the syringe with approximately 25 ml water and approximately 5 ml air.

For some tubes, dispersion in 50 ml water is needed to prevent the pellets from clogging the tube.

2. Immediately shake the syringe to evenly distribute the granules throughout the suspension.

3. Hold the syringe with the tip up and check that the tip has not clogged.

4. Attach the syringe to the tube whilst maintaining the above position.

5. Shake the syringe and position it with the tip pointing down. Immediately inject 5 – 10 ml into the tube. Invert the syringe after injection and shake (the syringe must be held with the tip pointing up to avoid clogging of the tip)

6. Turn the syringe with the tip down and immediately inject another 5 – 10 ml into the tube. Repeat this procedure until the syringe is empty.

7. Fill the syringe with 25 ml of water and 5 ml of air and repeat step 5 if necessary to wash down any sediment left in the syringe. For some tubes, 50 ml water is needed.

7. Marketing Authorisation Holder

Consilient Health Ltd.

5^th Floor, Beaux Lane House,

Mercer Street Lower, Dublin 2,

Ireland.

8. Marketing Authorisation Number(S)

PL 24837/0031

9. Date Of First Authorisation/Renewal Of The Authorisation

12/07/2010

10. Date Of Revision Of The Text

March 2011

Induxin

Induxin may be available in the countries listed below.

Ingredient matches for Induxin

Oxytocin

Oxytocin is reported as an ingredient of Induxin in the following countries:

• Indonesia


• Myanmar

International Drug Name Search

Baby Meltus Cough Linctus

1. Name Of The Medicinal Product

Baby Meltus Cough Linctus.

2. Qualitative And Quantitative Composition

Dilute Acetic Acid BP 0.42 ml/5ml.

3. Pharmaceutical Form

Syrup for oral use.

4. Clinical Particulars

4.1 Therapeutic Indications

For the symptomatic relief of the irritating and distressing coughs which often accompany colds.

4.2 Posology And Method Of Administration

Oral. To be given slowly. 3 months to one year: half a 5 ml spoonful. Over one year: one 5 ml spoonful. Over two and a half years: two 5 ml spoonfuls. Repeat as necessary every 2 to 3 hours.

4.3 Contraindications

None known.

4.4 Special Warnings And Precautions For Use

Keep out of reach of children.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

Not applicable.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

At the level of acetic acid in this product, none are known.

4.9 Overdose

Not applicable. Treatment: Not applicable

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Baby Meltus Cough Linctus contains acetic acid - a mild expectorant in a sugar free blackcurrant flavoured demulcent base.

5.2 Pharmacokinetic Properties

Not applicable.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tolu Flavour Solution - sugar free; Sorbitol Solution Non Crystallising; Carmellose Sodium; Imitation Blackcurrant Flavour 500013E; Blackcurrant Flavour C3688; Sodium Saccharin; Methylhydroxybenzoate; Propylhydroxybenzoate; Water.

6.2 Incompatibilities

None.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

Amber glass sirop bottle with tamper evident cap with fitted polycone liner in an outer carton containing 100 ml of product. Supplied with a 5ml CE marked polystyrene measuring spoon.

6.6 Special Precautions For Disposal And Other Handling

None known.

7. Marketing Authorisation Holder

Cupal Ltd, Venus, 1 Old Park Lane, Trafford Park, Manchester, M41 7HA, UK

8. Marketing Authorisation Number(S)

PL 0338/0059.

9. Date Of First Authorisation/Renewal Of The Authorisation

9^th October 1986 / 29^th May 2003.

10. Date Of Revision Of The Text

September 2007

Micotil 300

Dosage Form: FOR ANIMAL USE ONLY
Micotil ® 300 Injection

Tilmicosin Injection, USP

NADA 140-929, Approved by FDA

AH0230

Caution:

Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

Description:

Micotil® is a solution of the antibiotic tilmicosin. Each mL contains 300 mg of tilmicosin, USP as tilmicosin phosphate in 25% propylene glycol, phosphoric acid as needed to adjust pH and water for injection, Q.S. Tilmicosin, USP is produced semi-synthetically and is in the macrolide class of antibiotics.

Indications:

Micotil is indicated for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida and Histophilus somni and for the treatment of ovine respiratory disease (ORD) associated with Mannheimia haemolytica. Micotil is indicated for the control of respiratory disease in cattle at high risk of developing BRD associated with Mannheimia haemolytica.

Dosage and Administration:

Inject Subcutaneously in Cattle and Sheep Only. In cattle, administer a single subcutaneous dose of 10 to 20 mg/kg of body weight (1 to 2 mL/30 kg or 1.5 to 3 mL per 100 lbs). In sheep greater than 15 kg, administer a single subcutaneous dose of 10 mg/kg of body weight (1 mL/30 kg or 1.5 mL per 100 lbs).

Do not inject more than 10 mL per injection site.

If no improvement is noted within 48-hours, the diagnosis should be reevaluated.

For cattle and sheep, injection under the skin in the neck is suggested. If not accessible, inject under the skin behind the shoulders and over the ribs.

Note: Swelling at the subcutaneous site of injection may be observed.

Contraindications:

Do not use in automatically powered syringes. Do not administer intravenously to cattle or sheep. Do not use in lambs less than 15 kg body weight. Intravenous injection in cattle or sheep will be fatal. Do not administer to animals other than cattle or sheep. Injection of this antibiotic has been shown to be fatal in swine and non-human primates, and it may be fatal in horses and goats.

Warnings:

Human Warnings: Not for human use. Injection of this drug in humans has been associated with fatalities. Keep out of reach of children. Do not use in automatically powered syringes. Exercise extreme caution to avoid accidental self-injection. In case of human injection, consult a physician immediately and apply ice or cold pack to injection site while avoiding direct contact with the skin. Emergency medical telephone numbers are 1-800-722-0987 or 1-800-428-4441. Avoid contact with eyes.

Note To the Physician: The cardiovascular system is the target of toxicity and should be monitored closely. Cardiovascular toxicity may be due to calcium channel blockade. In dogs, administration of intravenous calcium offset Micotil-induced tachycardia and negative inotropy (decreased contractility). Dobutamine partially offset the negative inotropic effects induced by Micotil in dogs. β-adrenergic antagonists, such as propranolol, exacerbated the negative inotropy of Micotil in dogs.

Epinephrine potentiated lethality of Micotil in pigs. This antibiotic persists in tissues for several days.

Residue Warnings: Animals intended for human consumption must not be slaughtered within 42 days of the last treatment. Not for use in lactating dairy cattle 20 months of age or older. Use of tilmicosin in this class of cattle may cause milk residues. Not for use in lactating ewes producing milk for human consumption.

For Subcutaneous Use in Cattle and Sheep Only. Do Not Use in Automatically Powered Syringes.

Precautions:

Read accompanying literature fully before use. Intramuscular injection will cause a local reaction which may result in trim loss of edible tissue at slaughter. The effects of tilmicosin on bovine and ovine reproductive performance, pregnancy and lactation have not been determined.

Adverse Reactions:

The following adverse reactions have been reported post-approval: In cattle: injection site swelling and inflammation, lameness, collapse, anaphylaxis/anaphylactoid reactions, decreased food and water consumption, and death.

In sheep: dyspnea and death.

For a complete listing of adverse reactions for tilmicosin phosphate reported to the CVM see http://www.fda.gov/AnimalVeterinary/SafetyHealth/ProductSafetyInformation/ucm055394.htm

Clinical Pharmacology:

A single subcutaneous injection of Micotil at 10 mg/kg of body weight dose in cattle resulted in peak tilmicosin levels within one hour and detectable levels (0.07 μg/mL) in serum beyond 3 days. However, lung concentrations of tilmicosin remained above the tilmicosin MIC 95% of 3.12 μg/mL for Mannheimia haemolytica for at least 3 days following the single injection. Serum tilmicosin levels are a poor indicator of total body tilmicosin. The lung/serum tilmicosin ratio in favor of lung tissue appeared to equilibrate by 3 days post-injection at approximately 60. In a study with radioactive tilmicosin, 24% and 68% of the dose was recovered from urine and feces respectively over 21 days. After a single subcutaneous injection of Micotil at 10 mg/kg of body weight, tilmicosin concentrations in excess of 4 μg/mL were maintained in the alveolar macrophages and neutrophils of most cattle for at least 10 days. The clinical relevance of these findings has not been determined.

Microbiology: Tilmicosin has an in vitro antibacterial spectrum that is predominantly Gram-positive with activity against certain Gram-negative microorganisms. In vitro activity against several Mycoplasma species has also been observed.

Effectiveness: In a multi-location field study, 1508 calves with naturally occurring BRD were treated with Micotil. Responses to treatment were compared to saline-treated controls. A cure was defined as a calf with normal attitude and activity, normal respiration, and a rectal temperature of <104°F on Day 13. The cure rate was significantly higher (P=0.004) in Micotil-treated calves (63.1%) compared to saline-treated calves (29.2%). During the treatment phase of the study, there were 10 BRD-related deaths in the Micotil-treated calves compared to 47 in the saline-treated calves.

Animal Safety: A safety study was conducted in feeder calves receiving subcutaneous doses of 20, 30, 40, or 60 mg/kg of body weight, injected 3 times at 72-hour intervals. Death was not seen in any of the treatment groups. Injection site swelling and mild hemorrhage at the injection site were seen in animals in all dosage groups. Lesions were described as being generally more severe and occurred at higher frequency rates in the animals treated with higher doses of tilmicosin. Lameness associated with the injection site was noted in two of twenty-four animals (one animal in the 30 mg/kg body weight treatment group and one animal in the 60 mg/kg treatment group). No other drug related lesions were observed macroscopically or microscopically. Decreases in food and water consumption were noted in all treatment groups compared to the control group.

A separate safety study conducted in feeder calves, subcutaneous doses of 10, 30, or 50 mg/kg of body weight, injected 3 times at 72-hour intervals did not cause any deaths. Edema at the site of injection was noted. The only lesion observed at necropsy was minimal myocardial necrosis in some animals dosed at 50 mg/kg.

In an additional safety study, subcutaneous doses of 150 mg/kg body weight injected at 72-hour intervals resulted in death of two of the four treated animals. Edema was marked at the site of injection. Minimal myocardial necrosis was the only lesion observed at necropsy. Deaths of cattle have been observed with a single intravenous dose of 5 mg/kg of body weight.

In sheep, single subcutaneous injections of 10 mg/kg body weight dose did not cause any deaths and no adverse effects of tilmicosin were observed on blood pressure, heart rate, or respiratory rate.

Toxicology: The heart is the target of toxicity in laboratory and domestic animals given Micotil by oral or parenteral routes. The primary cardiac effects are increased heart rate (tachycardia) and decreased contractility (negative inotropy). Cardiovascular toxicity may be due to calcium channel blockade.

Upon subcutaneous injection, the acute median lethal dose of tilmicosin in mice is 97 mg/kg, and in rats is 185 mg/kg of body weight. Given orally, the median lethal dose is 800 mg/kg and 2250 mg/kg body weight in fasted and nonfasted rats, respectively. No compound-related lesions were found at necropsy.

In dogs, intravenous calcium offset Micotil-induced tachycardia and negative inotropy, restoring arterial pulse pressure. Dobutamine partially offset the negative inotropic effects induced by Micotil in dogs. Β-adrenergic antagonists, such as propranolol, exacerbated the negative inotropy of Micotil in dogs.

In monkeys, a single intramuscular dose of 10 mg/kg body weight caused no signs of toxicity. A single dose of 20 mg/kg body weight caused vomiting and 30 mg/kg body weight caused the death of the only monkey tested.

In swine, intramuscular injection of 10 mg/kg body weight caused increased respiration, emesis, and a convulsion, 20 mg/kg body weight resulted in mortality in 3 of 4 pigs, and 30 mg/kg body weight caused the death of all 4 pigs tested. Injection of 4.5 and 5.6 mg/kg body weight intravenously followed by epinephrine, 1mL (1:1000) intravenously 2 to 6 times, resulted in death of all pigs injected. Pigs given 4.5 mg/kg and 5.6 mg/kg body weight intravenously with no epinephrine all survived. These results suggest intravenous epinephrine may be contraindicated.

Results of genetic toxicology studies were all negative. Results of teratology and reproduction studies in rats were negative. The no effect level in dogs after daily oral doses for up to one year is 4 mg/kg of body weight.

Storage Conditions: Store at or below 86°F (30°C). Protect from direct sunlight.

How Supplied:

Micotil is supplied in 100 mL and 250 mL multi-dose amber glass bottles.

Elanco®, Micotil® and the diagonal bar are trademarks of Eli Lilly and Company.

Manufactured for:

Elanco Animal Health

A Division of Eli Lilly and Company

Indianapolis, IN 46285, USA

Revised JANUARY 2010

Micotil® 300

AH0230

PA9980DEAMX

SAFE HANDLING PRACTICES WHEN USING

MICOTIL® 300 TILMICOSIN INJECTION, USP

Please read this information before you start using Micotil. This information is a summary and is not intended to take the place of discussions with your veterinarian. Micotil can only be prescribed by a licensed veterinarian who has information specific to your operation. You should discuss with your veterinarian how to use Micotil, human warnings associated with the product and recommended safe handling and use practices. For emergency medical information call 1-800-722-0987 or 1-800-428-4441. If you have any questions about Micotil, talk with your veterinarian or call Elanco at 1-800-428-4441. To report an adverse drug event contact Elanco at 1-800-428-4441.

1. WHAT ARE THE POSSIBLE EFFECTS OF ACCIDENTAL HUMAN INJECTION?
   
   Human injections of Micotil have been associated with fatalities. Clinical signs from human exposure include off taste in the mouth, nausea, headache, dizziness, rapid heart rate, chest pain, anxiety or lightheadedness. Local reactions such as injection site pain, bleeding, swelling or inflammation have been reported.


2. WHAT SHOULD I DO IN THE CASE OF ACCIDENTAL HUMAN INJECTION?
   
   • Immediately seek medical attention.
   
   
   • Apply ice or cold pack to injection site, while avoiding direct contact with the skin, and transport immediately to a hospital.
   
   
   • Call 1-800-722-0987 or 1-800-428-4441 for further emergency information.
   
   


3. WHAT SHOULD MY PHYSICIAN KNOW IN THE CASE OF ACCIDENTAL HUMAN INJECTION?
   
   • The cardiovascular system is the target of toxicity and should be monitored closely.
   
   
   • Cardiovascular toxicity may be due to calcium channel blockade.
   
   
   • Intravenous calcium administration reversed the cardiovascular effects of Micotil in dogs and may provide benefit in patients exhibiting low blood pressure (hypotension) or rapid heart rate (tachycardia).
   
   
   • Dobutamine improved some of the cardiac function in dogs given Micotil.
   
   
   • Epinephrine increased the toxicity of Micotil in pigs, resulting in death.
   
   
   • Propranolol (a beta-adrenergicantagonist), further decreased cardiac function in dogs given Micotil.
   
   
   • The active ingredient in Micotil is tilmicosin phosphate and persists in tissue for several days.
   
   
   • Call 1-800-722-0987 or 1-800-428-4441 for further emergency information.
   
   


4. WHAT ARE THE PROPER WAYS TO HANDLE AND STORE MICOTIL?
   
   • Store at or below 86°F (30°C), out of direct sunlight, in a safe location, not easily accessible to the general public.
   
   
   • Read, understand and follow all label use directions.
   
   
   • Keep the needle capped until ready to use.
   
   
   • Never carry a loaded syringe with an attached needle in pocket or clothing.
   
   
   • Wash hands thoroughly with soap and water after handling.
   
   


5. WHAT ARE THE PROPER METHODS FOR ADMINISTERING MICOTIL?
   
   • Properly restrain animals prior to administration.
   
   
   • Work in a team, or if alone, advise someone of your location and how long you plan to be there.
   
   
   • For subcutaneous use. Do not use in automatically powered syringes.
   
   
   • Use a 1/2-inch to 5/8-inch, 18- to 16-gauge needle.
   
   
   • With a single hand on the syringe, insert the needle subcutaneously, at a top-down angle, while avoiding penetration of underlying muscle.
   
   
   • For cattle and sheep, injection under the skin in the neck is suggested. If not accessible, inject under the skin behind the shoulders and over the ribs.
   
   
   • Administer a single subcutaneous dose of 1.5 mL to 3.0 mL of Micotil per 100 lbs of body weight, in either of the two areas noted in the adjacent drawing.
     
     
     
   
   
   • For beef cattle, Beef Quality Assurance recommends injection site 1, unless this site is inaccessible or places the operator in a potentially dangerous situation.
   
   
   • Ensure proper disposal of sharp needles and syringes.
   
   
   • Wash hands thoroughly with soap and water after administration.
   
   
   • Do not administer intravenously (IV) as IV administration will be fatal.
   
   
   • Intramuscular injection will cause a local reaction, which may result in trim loss.
   
   
   • Do not inject more than 10 mL per injection site.
   
   
   • Do not use in lambs less than 15 kg body weight.
   
   

Issued January, 2010

Elanco Animal Health

• A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA

Elanco® and Micotil® are trademarks of Eli Lilly and Company.

Copyright © 2003, Elanco Animal Health.

PA9980DEAMX (V06-01-2010)

Principal Display Panel - 100 mL Bottle Label

Elanco® AH230-82X

For use in Cattle and Sheep Only

Micotil® 300

Tilmicosin Injection, USP

300 mg tilmicosin, USP as tilmicosin phosphate per mL

™

Do Not Use in Automatically Powered Syringes

NADA 140-929, Approved by FDA

UPC 7 2780420213

Principal Display Panel - 100 mL Carton Label

Elanco® AH0230-82X

For use in Cattle and Sheep Only

Micotil® 300

Tilmicosin Injection, USP

300 mg tilmicosin, USP as tilmicosin phosphate per mL

™

Do Not Use in Automatically Powered Syringes

Caution: Federal (USA) law restricts the drug to use by or on the order of a licensed veterinarian.

Description: Micotil® is a solution of the antibiotic Tilmicosin. Each mL contains 300 mg of tilmicosin, USP as tilmicosin phosphate in 25% propylene glycol, phosphoric acid as needed to adjust pH and water for injection, Q.S. Tilmicosin, USP is produced semi-synthetically and is in the macrolide class of antibiotics.

NADA 1 40-929

Approved by FDA

UPC 7 27804 202132 100 mL

Principal Display Panel - 250 mL Bottle Label

Elanco® AH0230-38W

For use in Cattle and Sheep Only

Micotil® 300

Tilmicosin Injection, USP

300 mg tilmicosin, USP as tilmicosin phosphate per mL

™

Do Not Use in Automatically Powered Syringes

Caution: Federal (USA) law restricts the drug to use by or on the order of a licensed veterinarian.

Description: Micotil® is a solution of the antibiotic Tilmicosin. Each mL contains 300 mg of tilmicosin, USP as tilmicosin phosphate in 25% propylene glycol, phosphoric acid as needed to adjust pH and water for injection, Q.S. Tilmicosin, USP is produced semi-synthetically and is in the macrolide class of antibiotics.

Indications: For the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida and Histophilus somni. For the treatment of ovine respiratory disease (ORD) associated with Mannheimia haemolytica. For the control of respiratory disease in cattle at high risk of developing BRD associated with Mannheimia haemolytica.

NADA 1 40-929, Approved by FDA

UPC 7 27804 202132 250 mL

Elanco®, Micotil® and the diagonal bar are trademarks of Eli Lilly and Company

Micotil 300  tilmicosin phosphate  injection, solution

Product Information Product Type PRESCRIPTION ANIMAL DRUG NDC Product Code (Source) 0986-0230 Route of Administration SUBCUTANEOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength TILMICOSIN PHOSPHATE (TILMICOSIN) TILMICOSIN PHOSPHATE 300 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength PROPYLENE GLYCOL   WATER

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0986-0230-02 1 BOTTLE In 1 CARTON contains a BOTTLE, GLASS 1 100 mL In 1 BOTTLE, GLASS This package is contained within the CARTON (0986-0230-02) 2 0986-0230-03 250 mL In 1 BOTTLE, GLASS None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NADA	NADA140929	02/19/2010

Labeler - Elanco Animal Health Co (807447169)

Establishment
Name	Address	ID/FEI	Operations
Norbrook Laboratories Limited		232880554	MANUFACTURE

Establishment
Name	Address	ID/FEI	Operations
Dottikon Exclusive Synthesis AG		480000413	API MANUFACTURE

Revised: 02/2010Elanco Animal Health Co

Beta-Cardone Tablets 80mg

1. Name Of The Medicinal Product

Beta-Cardone Tablets 80mg

Sotalol Hydrochloride Tablets 80mg

2. Qualitative And Quantitative Composition

Sotalol Hydrochloride 80mg

For excipients see 6.1.

3. Pharmaceutical Form

Tablet

Pink, circular, flat-faced tablets with bevelled edges, with “Evans/BC8” on one face.

4. Clinical Particulars

4.1 Therapeutic Indications

Ventricular arrhythmias: Treatment of life-threatening ventricular tachyarrhythmias and symptomatic non-sustained ventricular tachyarrhythmias.

Supraventricular arrhythmias: Prophylaxis of paroxysmal atrial tachycardia, paroxysmal atrial fibrillation, paroxysmal A-V nodal re-entrant tachycardia, paroxysmal A-V re-entrant tachycardia using accessory pathways, and paroxysmal supraventricular tachycardia after cardiac surgery. Maintenance of normal sinus rhythm following conversion of atrial fibrillation or atrial flutter.

4.2 Posology And Method Of Administration

Oral administration in adults:

When administering Beta-Cardone to a patient for the first time, it is desirable to start with a low dose and gradually increase the dose until the desired response is obtained; this is especially important in the elderly, as a general rule the heart rate should not be reduced to less than 55 beats per minute.

Before starting treatment or increasing the dose the corrected QT interval should be measured and renal function, electrolyte balance, and concomitant medications assessed. Treatment with sotalol should be initiated and doses increased in a facility capable of monitoring and assessing cardiac rhythm. The dosage must be individualised and based on the patient's response. Proarrhythmic events can occur not only at initiation of therapy, but also with each upward dosage adjustment.

Treatment with Beta-Cardone should not be discontinued suddenly, especially in patients with ischaemic heart disease (angina pectoris, prior acute myocardial infarction) or hypertension, to prevent exacerbation of the disease (see section “abrupt withdrawal” under Special Warnings).

The following are guidelines for oral administration.

The initial dose is 80mg, as one or two divided doses. Oral dosage should be adjusted gradually allowing 2-3 days between dosing increments in order to attain steady-state, and to allow monitoring of QT intervals. Most patients respond to 160 to 320mg per day, in two divided doses.

The dosage should be reduced in renal impairment. Creatinine clearance: 60-30ml/min.: ¹/₂ recommended dose. Creatinine clearance 30-10ml/min.: ¹/₄ recommended dose.

Administration in children:

Beta-Cardone is not intended for administration to children.

4.3 Contraindications

Sick sinus syndrome; long QT syndromes, Torsades de Pointes; symptomatic sinus bradycardia; uncontrolled congestive heart failure; cardiogenic shock; anaesthesia that produces myocardial depression; untreated phaeochromocytoma; hypotension (except due to arrhythmia); Raynaud's phenomenon and severe peripheral circulatory disturbances; chronic obstructive airway disease or bronchial asthma; renal failure (creatinine clearance <10 ml/min.).

Beta-Cardone should not be given to patients suffering from heart block or patients with Prinzmetal's angina and those who have a history of bronchospasm,

In patients with poor cardiac reserve beta-blockade can precipitate heart failure; in such cases, sotalol hydrochloride therapy should not be commenced until the patient has been controlled by therapy (ACE inhibitors, cardiac glycosides or, if necessary, diuretic therapy - see Interactions).

Diabetic ketoacidosis and metabolic acidosis: Sotalol hydrochloride should not be given to patients suffering from diabetic ketoacidosis or metabolic acidosis; therapy with sotalol hydrochloride can be commenced or resumed when the metabolic condition has been corrected.

Beta-Cardone should not be given to patients hypersensitive to sotalol.

4.4 Special Warnings And Precautions For Use

Beta-Cardone should not be given to patients who have a history of asthma or bronchospasm.

Beta-blockers may increase the sensitivity towards allergens and the seriousness of anaphylactic reactions.

Patients with a history of psoriasis should take beta-blockers only after careful consideration.

Abrupt withdrawal: Patients should be carefully monitored when discontinuing chronically administered sotalol, particularly those with ischaemic heart disease. If possible the dosage should be gradually reduced over a period of 1 to 2 weeks, if necessary at the same time initiating replacement therapy. Hypersensitivity to catecholamines is observed in patients withdrawn from beta-blocker therapy. Occasional cases of exacerbation of angina pectoris, arrhythmias and in some cases myocardial infarction have been reported after abrupt discontinuation of therapy. Abrupt discontinuation may unmask latent coronary insufficiency. In addition, hypertension may develop.

Proarrhythmias: Rarely, Beta-Cardone causes aggravation of pre-existing arrhythmias or the provocation of new arrhythmias.

Risk factors for Torsades de Pointes include prolongation of the QT interval, bradycardia, reduction in serum potassium and magnesium, and history of cardiomegaly or congestive heart failure, sustained ventricular tachycardia.

Proarrhythmic events can occur on initiating therapy and with every upward dose adjustment. The incidence of Torsades de Pointes is dose dependent.

Caution should be used if the QT_C exceeds 500 msec whilst on therapy. It is advisable to reduce dose or discontinue therapy when the QT_C interval exceeds 550 msec.

Electrolyte disturbances: Sotalol should not be used in patients with hypokalaemia or hypomagnesaemia. Potassium levels should be monitored. In conditions likely to provoke hypokalaemia/hypomagnesaemia, such as persistent diarrhoea, appropriate corrective clinical measures should be taken.

Heart failure:Beta-blockade may precipitate heart failure.

Following myocardial infarction careful monitoring and dose titration are critical during initiation and follow-up of therapy. Sotalol should be avoided in patients with left ventricular ejection fractions

Thyrotoxicosis:Beta-blockade may mask certain clinical signs of hyperthyroidism.

Treated diabetes: Beta-Cardone, like other beta-blocking agents, may reduce or mask the usual pre-hypoglycaemic warning signs. It may be necessary to adjust the dose of anti-diabetic therapy.

General anaesthesia: If desired, Beta-Cardone may be stopped four days prior to surgery. However, where sudden withdrawal might expose the patient to severe angina or arrhythmias, anaesthesia can proceed provided that the following precautions are taken.

1. Vagal dominance is counteracted by premedication with atropine sulphate (0.25 to 2.0mg) administered intravenously.

2. Anaesthetic agents such as ether, chloroform, cyclopropane, trichlorethylene, methoxyflurane and enflurane are not used.

Alcoholism: Beta-adrenoceptor blocking drugs may precipitate cardiac failure in alcoholic patients.

Upper respiratory infections: In these conditions patients without a history of airways obstruction may suffer bronchospasm from beta-blockade.

The product labelling will bear a statement warning against use in patients with a history of wheezing or asthma.

Patients with rare hereditary problems of galactose intolerance, the Lapp-lactose deficiency, or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In combined therapy, clonidine should not be discontinued until several days after withdrawal of Beta-Cardone.

Use with great caution with drugs that also prolong QT interval, e.g. disopyramide, amiodarone, class I antiarrhythmic agents, calcium antagonists of the verapamil type or tricyclic antidepressants.

Concomitant potassium-depleting diuretics may increase the potential for Torsade de Pointes.

Proarrhythmic events are more common in patients also receiving digitalis glycosides.

Phenothiazines, terfenadine, astemizole, diltiazem and halofantrine.

Concomitant use of reserpine, guanethidine, or alpha methyldopa: Closely monitor for evidence of hypotension and/or marked bradycardia, syncope.

Tubocurarine: Neuromuscular blockade is prolonged by beta-blocking agents.

Calcium antagonists: Dihydropyridine derivatives such as nifedipine. The risk of hypotension may be increased. In patients with latent cardiac insufficiency, concomitant treatment with beta-blockers may lead to cardiac failure.

Prostaglandin synthetase inhibiting drugs may decrease the hypotensive effects of beta-blockers.

Sympathicomimetic agents: may counteract the effect of beta-adrenergic agents.

Concomitant administration of tricyclic antidepressants, barbiturates and phenothiazines as well as other antihypertensive agents may increase the blood pressure lowering effect.

Precautions for use:

Insulin and oral antidiabetic drugs, may intensify the blood sugar lowering effect (especially non-selective beta-blockers).

Beta-adrenergic blockade may prevent the appearance of signs of hypoglycaemia

(tachycardia).

Cimetidine, hydralazine and alcohol induce increased levels of hepatically metabolised beta-blockers.

4.6 Pregnancy And Lactation

Use in pregnancy should be avoided.

Pregnancy: Animal studies with sotalol hydrochloride have shown no evidence of teratogenicity or other harmful effects on the foetus. Nevertheless its use throughout pregnancy should be avoided unless it is absolutely necessary as it crosses the placenta and may cause foetal bradycardia.

Beta-blockers reduce placental perfusion which may result in intrauterine foetal death, immature and premature deliveries. In addition, adverse effects (especially hypoglycaemia and bradycardia) may occur in the foetus and neonate. There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period. Most beta-blockers, particularly lipophilic compounds, will pass into breast milk although to a variable extent.

Lactation: Infants should not be fed with breast milk from mothers being treated with Beta-Cardone.

Newborns exposed near delivery should be closely observed for the first 24-48 hours for signs and symptoms of beta-blockade.

4.7 Effects On Ability To Drive And Use Machines

Side-effects such as dizziness and fatigue should be taken into account.

4.8 Undesirable Effects

The most significant adverse effects are those due to proarrhythmia, including Torsades de Pointes. There is an increased risk of Torsades de Pointes in women.

Also bradycardia, dyspnoea, chest pain, palpitations, oedema, ECG abnormalities, hypotension, proarrhythmia, syncope, heart failure, presyncope. Nausea/vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, cramps, fatigue, dizziness, asthenia, lightheadedness, headache, sleep disturbances, depression, paraesthesia, mood changes, anxiety, sexual dysfunction, visual disturbances, taste abnormalities, hearing disturbances, fever, slowed AV-conduction or increase of an existing AV-block, cold and cyanotic extremities, Raynaud's phenomenon, increase of intermittent claudication.

Beta-blockers, even those with apparent cardioselectivity should not be used in patients with asthma or a history of obstructive airways disease unless no alternative treatment is available. In such cases, the risk of inducing bronchospasm should be appreciated and appropriate precautions taken. If bronchospasm should occur after the use of Beta-Cardone it can be treated with a beta₂-agonist by inhalation e.g. salbutamol (the dose of which may need to be greater than the usual dose in asthma) and, if necessary, intravenous atropine 1mg.

There have been reports of skin rashes and especially exacerbation of psoriasis disorders of lacrimation including dry eyes and conjunctivitis. In most cases the symptoms have cleared when the treatment was withdrawn. Discontinuance of the drug should be considered if any such reaction is not otherwise explicable. Cessation of therapy with a beta-blocker should be gradual.

An increase in Anti Nuclear Antibodies has been seen; its clinical relevance is not clear.

4.9 Overdose

Symptoms of overdose are: bradycardia, hypotension, bronchospasm and acute cardiac insufficiency.

After ingestion of an overdose or in the case of hypersensitivity, the patient should be kept under close supervision and treated in an intensive care ward. Absorption of any drug material still present in the gastro-intestinal tract can be prevented by gastric lavage, administration of activated charcoal and a laxative. Artificial respiration may be required. Bradycardia or extensive vagal reactions should be treated by administering atropine or methylatropine. Hypotension and shock should be treated with plasma/plasma substitutes and if necessary, catecholamines. The beta-blocking effect can be counteracted by slow intravenous administration of isoprenaline hydrochloride, starting with a dose of approximately 5 micrograms/minute, or dobutamine, starting with a dose of 2.5 micrograms/minute, until the required effect has been obtained.

In refractory cases isoprenaline can be combined with dopamine. If this does not produce the desired effect either, Intravenous administration of 8-10 mg of glucagon may be considered. If required the injection should be repeated within one hour, to be followed - if required - by an i.v. infusion of glucagon at an administration rate of 1-3 mg/hour. Administration of calcium ions, or the use of a cardiac pacemaker may also be considered. In patients intoxicated with hydrophylic beta-blocking agents hemodialysis or hemoperfusion may be considered.

Prolongation of the QT_c interval has been reported. Transvenous pacing may be required.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Sotalol has both beta-adrenoreceptor blocking (Vaughan Williams Class II) and cardiac action potential duration prolongation (Vaughan Williams Class III) antiarrhythmic properties. The d- and l-isomers of sotalol have similar Class III antiarrhythmic effects while the l-isomer is responsible for virtually all of the beta-blocking activity.

5.2 Pharmacokinetic Properties

Sotalol is completely absorbed from the gastrointestinal tract and peak plasma concentrations are obtained about 2 or 3 hours after a dose. It is excreted unchanged in the urine. After oral administration the plasma half-life has been shown to be 17 hours. It is not bound to plasma proteins. The lipid solubility is very low.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose

Maize Starch

Pregelatinised Starch

Talc

Magnesium Stearate

Dispersed Red 11652

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Beta-Cardone Tablets should be protected from light.

6.5 Nature And Contents Of Container

Polypropylene securitainers containing 100 or 500 tablets.

PVC, PVdC and foil blister pack containing 56 tablets.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Celltech Pharmaceuticals Limited

208 Bath Road

Slough

Berkshire

SL1 3WE

UK

8. Marketing Authorisation Number(S)

PL 00039/0415

9. Date Of First Authorisation/Renewal Of The Authorisation

12 January 1993/11 May 2000

10. Date Of Revision Of The Text

December 2003

POM