Metformin 850mg

1. Name Of The Medicinal Product

Metformin hydrochloride 850 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 850 mg metformin hydrochloride corresponding to 663 mg metformin.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

White, round, biconvex, film-coated tablets with 'A' debossed on one side and '61' debossed on the other side.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of type 2 diabetes mellitus, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycemic control.

• In adults, Metformin film-coated tablets may be used as monotherapy or in combination with other oral anti-diabetic agents or with insulin.

• In children from 10 years of age and adolescents, Metformin hydrochloride film-coated tablets may be used as monotherapy or in combination with insulin.

A reduction of diabetic complications has been shown in overweight type 2 diabetic adult patients treated with metformin hydrochloride as first-line therapy after diet failure (see section 5.1).

4.2 Posology And Method Of Administration

Adults:

Monotherapy and combination with other oral antidiabetic agents:

- The usual starting dose is 500mg or 850mg metformin hydrochloride 2 or 3 times daily given during or after meals.

After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability.

The maximum recommended dose of metformin hydrochloride is 3 g daily, taken as 3 divided doses.

If transfer from another oral antidiabetic agent is intended: discontinue the other agent and initiate metformin hydrochloride at the dose indicated above.

Combination with insulin:

Metformin hydrochloride and insulin may be used in combination therapy to achieve better blood glucose control. Metformin hydrochloride is given at the usual starting dose of 500mg or 850mg metformin hydrochloride 2or3 times daily, while insulin dosage is adjusted on the basis of blood glucose measurements.

Elderly:

Due to the potential for decreased renal function in elderly subjects, the metformin hydrochloride dosage should be adjusted based on renal function. Regular assessment of renal function is necessary (see section 4.4).

Children and adolescents:

Monotherapy and combination with insulin

• Metformin hydrochloride film-coated tablets can be used in children from 10 years of age and adolescents.

• The usual starting dose is 500 mg or 850 mg metformin hydrochloride once daily, given during meals or after meals.

After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. The maximum recommended dose of metformin hydrochloride is 2 g daily, taken as 2 or 3 divided doses.

4.3 Contraindications

• Hypersensitivity to metformin hydrochloride or to any of the excipients.

• Diabetic ketoacidosis, diabetic pre-coma.

• Renal failure or renal dysfunction (creatinine clearance < 60 ml/min).

• Acute conditions with the potential to alter renal function such as:
	dehydration,
	severe infection,
	shock,
	intravascular administration of iodinated contrast agents (see section 4.4).

• Acute or chronic disease which may cause tissue hypoxia such as:
	cardiac or respiratory failure,
	recent myocardial infarction,
	shock

• Hepatic insufficiency, acute alcohol intoxication, alcoholism

• Lactation.

4.4 Special Warnings And Precautions For Use

Lactic acidosis:

Lactic acidosis is a rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin hydrochloride accumulation. Reported cases of lactic acidosis in patients on metformin hydrochloride have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by assessing also other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia.

Diagnosis:

The risk of lactic acidosis must be considered in the event of non-specific signs such as muscle cramps with digestive disorders as abdominal pain and severe asthenia.

Lactic acidosis is characterised by acidotic dyspnea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5mmol/l, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, metformin hydrochloride should be discontinued and the patient should be hospitalised immediately (see section 4.9).

Renal function:

As metformin hydrochloride is excreted by the kidney, serum creatinine levels should be determined before initiating treatment and regularly thereafter:

* at least annually in patients with normal renal function,

* at least two to four times a year in patients with serum creatinine levels at the upper limit of normal and in elderly subjects.

Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diueretic therapy and when starting therapy with a non-steroidal anti-inflammatory drug.

Administration of iodinated contrast agent:

As the intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure, metformin hydrochloride must be discontinued prior to, or at the time of the test and not be reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see section 4.5).

Surgery:

Metformin hydrochloride must be discontinued 48 hours before elective surgery under general, spinal or peridural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and only if normal renal function has been established.

Children and adolescents:

The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with metformin hydrochloride is initiated.

No effect of metformin hydrochloride on growth and puberty has been detected during controlled clinical studies of one-year duration but no long-term data on these specific points are available. Therefore, a careful follow-up of the effect of metformin hydrochloride on these parameters in metformin hydrochloride-treated children, especially pre-pubescent children, is recommended.

Children aged between 10 and 12 years:

Only 15 subjects aged between 10 and 12 years were included in the controlled clinical studies conducted in children and adolescents. Although efficacy and safety of metformin hydrochloride in these children did not differ from efficacy and safety in older children and adolescents, particular caution is recommended when prescribing to children aged between 10 and 12 years.

Other precautions:

All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.

The usual laboratory tests for diabetes monitoring should be performed regularly.

Metformin hydrochloride alone does not cause hypoglycaemia, but caution is advised when it is used in combination with insulin or sulfonylureas.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use not recommended

Alcohol:

Increased risk of lactic acidosis in acute alcohol intoxication, particularly in case of:
	fasting or malnutrition;
	hepatic insufficiency.

Avoid consumption of alcohol and alcohol-containing medicinal product.

Iodinated contrast agents (see section 4.4):

Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in metformin hydrochloride accumulation and an increased risk of lactic acidosis.

Metformin hydrochloride must be discontinued prior to, or at the time of the test and not be reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.

Combinations requiring precautions for use:

Glucocorticoids (systemic and local routes), beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. Inform the patient and perform more frequent blood glucose monitoring, especially at the beginning of treatment. If necessary, adjust the dosage of the antidiabetic medicinal product during therapy with the other medicinal product and upon its discontinuation.

ACE-inhibitors may decrease the blood glucose levels. Therefore, dose adjustment of metformin hydrochloride may be necessary during and after addition or discontinuation of such medicinal products.

4.6 Pregnancy And Lactation

Use in pregnancy:

To date, no relevant epidemiological data are available. Animal studies do not indicate harmful effects with respect to pregnancy, embryonal or fetal development, parturition or postnatal development (see section 5.3).

When a woman plans to become pregnant and during pregnancy, diabetes should not be treated with metformin hydrochloride but insulin should be used to maintain blood glucose levels as close to normal as possible in order to lower the risk of fetal malformations associated with abnormal blood glucose levels.

Use in lactation:

Metformin hydrochloride is contra-indicated during lactation.

Meformin hydrochloride is excreted into milk in lactating rats. Similar data are not available in humans and a decision should be made whether to discontinue breast-feeding or to discontinue metformin hydrochloride, taking into account the importance of the medicinal product to the mother.

4.7 Effects On Ability To Drive And Use Machines

Metformin hydrochloride monotherapy does not cause hypoglycaemia and therefore has no effect on the ability to drive or to use machines.

However, patients should be alerted to the risk of hypoglycaemia when meformin hydrochloride is used in combination with other antidiabetic agents (sulfonylureas, insulin, repaglinide).

4.8 Undesirable Effects

The following undesirable effects may occur under treatment with metformin hydrochloride. Frequencies are defined as follows:

Very common (

Common (

Uncommon (

Rare (

Very rare (< 1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Nervous system disorders:
Common:	Taste disturbance
Gastrointestinal disorders:
Very common:	Gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite. These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that metformin hydrochloride be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.
Skin and subcutaneous tissue disorders:
Very rare:	Skin reactions such as erythema, pruritus and urticaria.
Metabolism and nutrition disorders:
Very rare:	Lactic acidosis (see section 4.4.).
Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of metformin hydrochloride. Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia.
Hepatobiliary disorders:
Not known:	Isolated reports of liver function tests abnormalities or hepatitis resolving upon metformin hydrochloride discontinuation.
In published and post marketing data and in controlled clinical studies in a limited paediatric population aged 10-16 years treated during 1 year, adverse event reporting was similar in nature and severity to that reported in adults.

4.9 Overdose

Hypoglycaemia has not been seen with metformin hydrochloride doses of up to 85 g, although lactic acidosis has occurred in such circumstances. High overdose of metformin hydrochloride or concomitant risks may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin hydrochloride is haemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Blood Glucose lowering drugs, excl Insulins, Biguanides

ATC code: A10BA02

Metformin hydrochloride is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.

Metformin hydrochloride may act via 3 mechanisms:

(1) reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis

(2) in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization

(3) and delay of intestinal glucose absorption.

Metformin hydrochloride stimulates intracellular glycogen synthesis by acting on glycogen synthase.

Metformin hydrochloride increases the transport capacity of all types of membrane glucose transporters (GLUTs) known to date.

In humans, independently of its action on glycaemia, metformin hydrochloride has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin hydrochloride reduces total cholesterol, LDL cholesterol and triglyceride levels.

Clinical efficacy:

The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in adult patients with type 2 diabetes.

Analysis of the results for overweight patients treated with metformin hydrochloride after failure of diet alone showed:

a significant reduction of the absolute risk of any diabetes-related complication in the metformin hydrochloride group (29.8 events/ 1000 patient-years) versus diet alone (43.3 events/ 1000 patient-years), p=0.0023, and versus the combined sulfonylurea and insulin monotherapy groups (40.1 events/ 1000 patient-years), p=0.0034;

a significant reduction of the absolute risk of diabetes-related mortality: metformin hydrochloride 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p=0.017;

a significant reduction of the absolute risk of overall mortality: metformin hydrochloride 13.5 events/ 1000 patient-years versus diet alone 20.6 events/ 1000 patient –years (p=0.011), and versus the combined sulfonylurea and insulin monotherapy groups 18.9 events/ 1000 patient-years (p=0.021);

a significant reduction in the absolute risk of myocardial infarction: metformin hydrochloride 11 events/ 1000 patient-years, diet alone 18 events/ 1000 patient-years (p=0.01)

Benefit regarding clinical outcome has not been shown for metformin hydrochloride used as second-line therapy, in combination with a sulfonylurea.

In type 1 diabetes, the combination of metformin hydrochloride and insulin has been used in selected patients, but the clinical benefit of this combination has not been formally established.

Controlled clinical studies in a limited paediatric population aged 10-16 years treated during 1 year demonstrated a similar response in glycaemic control to that seen in adults.

5.2 Pharmacokinetic Properties

Absorption:

After an oral dose of metformin hydrochloride, T_max is reached in 2.5 hours. Absolute bioavailability of a 500 mg or 850 mg metformin hydrochloride tablet is approximately 50-60 % in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30 %.

After oral administration, metformin hydrochloride absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin hydrochloride absorption is non-linear.

At the recommended metformin hydrochloride doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1 microgram/ml. In controlled clinical trials, maximum metformin hydrochloride plasma levels (C_max) did not exceed 4 microgram/ml, even at maximum doses.

Food decreases the extent and slightly delays the absorption of metformin hydrochloride. Following administration of a dose of 850 mg, a 40 % lower plasma peak concentration, a 25 % decrease in AUC (area under the curve) and a 35 minute prolongation of time to peak plasma concentration were observed. The clinical relevance of these findings is unknown.

Distribution:

Plasma protein binding is negligible. Metformin hydrochloride partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution (Vd) ranged between 63-276 l.

Metabolism:

Metformin hydrochloride is excreted unchanged in the urine. No metabolites have been identified in humans.

Elimination:

Renal clearance of metformin hydrochloride is >400 ml/min, indicating that metformin hydrochloride is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.

When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin hydrochloride in plasma.

Children and adolescents:

Single dose study: After single doses of metformin hydrochloride 500 mg, paediatric patients have shown similar phamacokinetic profile to that observed in healthy adults.

Multiple dose study: Data are restricted to one study. After repeated doses of 500 mg twice daily for 7 days in paediatric patients the peak plasma concentration (C_max) and systemic exposure (AUC_0-t) were reduced by approximately 33% and 40%, respectively compared to diabetic adults who received repeated doses of 500 mg twice daily for 14 days. As the dose is individually titrated based on glycaemic control, this is of limited clinical relevance.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies on safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and reproductive toxicity.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

Povidone

Magnesium stearate

Film-coating:

Hypromellose

Macrogol

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

4 years

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

20, 28, 30, 40, 42, 50, 56, 60, 70, 80, 84, 90, 98, 100, 120, 180, 200, 300 or 400 film-coated tablets in blister packs (PVC / PVdC / aluminium), each blister containing 10 or 14 film-coated tablets.

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 off in accordance with local requirements.

7. Marketing Authorisation Holder

Aurobindo Pharma Limited

Ares, Odyssey Business Park

West End Road

South Ruislip HA4 6QD

United Kingdom

8. Marketing Authorisation Number(S)

PL 20532-0174

9. Date Of First Authorisation/Renewal Of The Authorisation

20/03/2009

10. Date Of Revision Of The Text

22/07/2010

Lyrinel XL prolonged release tablet

1. Name Of The Medicinal Product

Lyrinel XL 5 mg prolonged release tablet

Lyrinel XL 10 mg prolonged release tablet

2. Qualitative And Quantitative Composition

Each prolonged release tablet contains 5 mg of oxybutynin hydrochloride

Each prolonged release tablet contains 10 mg of oxybutynin hydrochloride

Excipient: Each Lyrinel XL prolonged release tablet contains 0.03 mg lactose.

For a full list of excipients, see Section 6.1.

3. Pharmaceutical Form

Prolonged release tablet.

Lyrinel XL 5 mg: Round yellow coloured tablet printed with “5 XL" on one side in black ink.

Lyrinel XL 10 mg: Round pink coloured tablet printed with “10 XL" on one side in black ink.

4. Clinical Particulars

4.1 Therapeutic Indications

Adults and Elderly

For the symptomatic treatment of urge incontinence and/or increased urinary frequency associated with urgency as may occur in patients with unstable bladder.

Paediatric population

Oxybutynin hydrochloride is indicated in children over 5 years of age for:

- Urinary incontinence, urgency and frequency in unstable bladder conditions due to idiopathic overactive bladder or neurogenic bladder disorders (detrusor overactivity).

- Nocturnal enuresis associated with detrusor overactivity, in conjunction with nondrug therapy, when other treatment has failed.

4.2 Posology And Method Of Administration

Dosage

Adults and Elderly

Starting dose: the recommended starting dose is one 5 mg tablet once daily.

Maintenance dose/dose adjustment: In order to achieve a maintenance dose giving an optimal balance of efficacy and tolerability, after at least one week on 5 mg daily, the dose may be increased to 10 mg once daily, with subsequent incremental increases or decreases of 5 mg/day. There should be an interval of at least one week between dose changes.

Maximum dose: in patients requiring a higher dose, the total daily dose should not exceed 20 mg.

For patients currently taking oxybutynin immediate release, clinical judgement should be exercised in selecting the appropriate dose of Lyrinel XL. The dosage should be adjusted to the minimum dose that achieves an optimal balance of efficacy and tolerability, taking into account the current immediate-release dose.

Children over the age of 5 years

Initial dose of 5 mg once a day increased in 5 mg increments up to a maximum of 15 mg once a day.

Lyrinel XL is not recommended for use in children below age of 5 years, due to a lack of data on safety and efficacy (see sections 5.1 and 5.2).

Method of administration

Lyrinel XL must be swallowed whole with the aid of liquid, and must not be chewed, divided, or crushed.

Patients should be advised that the tablet membrane may pass through the gastrointestinal tract unchanged. This has no bearing on the efficacy of the product.

Lyrinel XL may be administered with or without food (see section 5.2).

4.3 Contraindications

- Hypersensitivity to oxybutynin or any of the excipients

- Narrow-angle glaucoma or shallow anterior chamber

- Myasthenia gravis

- Urinary retention

- Gastrointestinal obstructive disorder, paralytic ileus or intestinal atony

- Severe ulcerative colitis

- Toxic megacolon

- Urinary frequency and nocturia due to heart or renal failure

- Porphyria

4.4 Special Warnings And Precautions For Use

Oxybutynin is associated with anticholinergic central nervous system (CNS) effects (see section 4.8 Undesirable Effects). Patients should be monitored for signs of anticholinergic CNS effects, particularly in the first few months after beginning treatment or increasing the dose. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

Oxybutynin should be given with caution in patients with the following conditions:

- hepatic or renal impairment

- clinically significant bladder outflow obstruction since anticholinergic drugs may aggravate bladder outflow and cause retention (see section 4.3)

- gastrointestinal motility disorders (see section 4.3)

- gastroesophageal reflux and/or who are currently taking drugs (such as bisphosphonates) that can cause or exacerbate esophagitis

- pre-existing dementia treated with cholinesterase inhibitors due to risk of aggravation of symptoms.

Oxybutynin should be used with caution in the frail elderly who may be more sensitive to the effects of oxybutynin.

If urinary tract infection is present, an appropriate antibacterial therapy should be started.

Oxybutynin may aggravate the symptoms of hyperthyroidism, congestive heart failure, cardiac arrhythmia, tachycardia, hypertension and prostatic hypertrophy.

When oxybutynin is used in patients with fever or in high environmental temperatures, this can cause heat prostration, or heat stroke, due to decreased sweating.

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

Oxybutynin may lead to decreased salivary secretions, which could result in tooth caries, periodontitis, or oral candidiasis.

As oxybutynin may trigger angle-closure glaucoma, visual acuity and intraocular pressure should be monitored periodically during therapy. Patients should be advised to seek advice immediately if they are aware of a sudden loss of visual acuity.

Paediatric population

Oxybutynin hydrochloride is not recommended for use in children below age 5 years due to insufficient data on safety and efficacy.

There is limited evidence supporting the use of Oxybutynin in children with monosymptomatic nocturnal enuresis (not related to detrusor overactivity).

In children over 5 years of age, Oxybutynin hydrochloride should be used with caution as they may be more sensitive to the effects of the product, particularly the CNS and psychiatric adverse reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The concomitant use of oxybutynin with other anticholinergic medicinal products or drugs with anticholinergic activity, such as amantadine and other anticholinergic antiparkinsonian drugs (e.g. biperiden, levodopa), antihistamines, antipsychotics (e.g. phenothiazines, butyrophenones, clozapine), quinidine, tricyclic antidepressants, atropine and related compounds like atropinic antispasmodics, dipyridamole, may increase the frequency or severity of dry mouth, constipation and drowsiness.

Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. They may also antagonize the gastrointestinal prokinetic effects of metoclopramide and domperidone. However, the interaction between prokinetics and oxybutynin has not been established.

Sublingual nitrates may fail to dissolve under the tongue owing to dry mouth, resulting in reduced therapeutic effect.

Oxybutynin is metabolised by cytochrome P450 isoenzyme CYP3A4. Mean oxybutynin chloride concentrations were approximately 2 fold higher when Lyrinel XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g. itraconazole and fluconazole) or macrolide antibiotics (e.g. erythromycin), may alter oxybutynin pharmacokinetics. The clinical relevance of such potential interaction is not known. Caution should be used when such drugs are co administered.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data on the use of oxybutynin in pregnant women. Studies in animals have shown minor reproductive toxicity (see section 5.3). Lyrinel XL should only be used during pregnancy if the expected benefit outweighs the risk.

Lactation

When oxybutynin is used during lactation, a small amount is excreted in the mother's milk. Breast feeding while using oxybutynin is therefore not recommended.

4.7 Effects On Ability To Drive And Use Machines

As oxybutynin may produce drowsiness or blurred vision, patients should be cautioned regarding activities requiring mental alertness such as driving, operating machinery or performing hazardous work while taking this drug.

4.8 Undesirable Effects

The table below reflects the data obtained with Lyrinel XL in clinical trials and from postmarketing experience. In clinical trials with Lyrinel XL (n=1006), adverse events were associated mainly with the anticholinergic actions of oxybutynin. Adverse events were generally dose related. As with other oxybutynin formulations, dry mouth was the most frequently reported adverse reaction. However, in clinical studies, dry mouth has been less frequently reported with Lyrinel XL than with oxybutynin immediate release formulations. For patients who required final doses of 5 or 10 mg of Lyrinel XL, the relative incidence of dry mouth that occurred at any dose level was 1.8 times lower compared with patients who required final doses > 10 mg.

	Very Common	Common	Uncommon	Rare	Not Known*
Infections and infestations		urinary tract infection, cystitis, pharyngitis, nasopharyngitis, upper respiratory tract infection,, bronchitis, sinusitis,
Blood and Lymphatic system disorders:				leukopenia, thrombocytopenia
Immune System Disorders				hypersensitivity
Metabolism & Nutrition Disorders			anorexia, dehydration, hyperglycaemia	appetite increased
Psychiatric disorders		insomnia, depression, nervousness, confusional state	anxiety, abnormal dreams		hallucinations, night terror, psychotic disorder, agitation,memory impairment
Nervous System Disorders		somnolence, headache, dizziness, dysgeusia	paraesthesia, vertigo	hypertonia, tremor, tinnitus	convulsions
Eye disorders		vision blurred, dry eye, kerato-conjunctivitis sicca	conjunctivitis	diplopia, glaucoma, photophobia
Cardiac disorders		palpitations		atrial arrhythmia, bradycardia, bundle branch block, nodal arrhythmia, supraventricular extrasystoles	arrhythmia tachycardia
Vascular disorders		hypertension	vasodilatation, migraine	hypotension, phlebitis, ecchymosis	flushing
Respiratory, thoracic and mediastinal disorders		nasal dryness, mucosal dryness, cough, pharyngo-laryngeal pain, dry throat	rhinitis, hoarseness, epistaxis, dyspnoea	laryngitis, laryngeal oedema, respiratory disorder, sputum increased
Gastrointestinal Disorders	dry mouth	constipation, diarrhoea, nausea, dyspepsia, abdominal pain, flatulence, gastroesophageal reflux disease, loose stools, vomiting	dysphagia, mouth ulceration, abdominal distension, glossitis, stomatitis	faecal abnormality, oesophageal stenosis acquired, gastritis, gastroenteritis viral, hernia, rectal disorder, gastric atony, tongue disorder, tongue oedema
Skin and subcutaneous tissue disorders		dry skin, pruritus	acne, urticaria, face oedema, alopecia, eczema, nail disorder, skin discolouration, anhidrosis	hair disorder, rash maculo-papular, granuloma, sweating increased, photosensitivity reaction	rash
Musculoskeletal and connective tissue disorders		pain in extremity, back pain, arthralgia	muscle cramps, myalgia	arthritis
Renal and urinary disorders		micturition disorder, residual urine volume, urinary retention, dysuria, urinary hesitation	urinary frequency, urinary tract disorder, haematuria, nocturia, pyuria, micturition urgency	urinary incontinence, urine abnormal, urogenital disorder	impotence, erectile dysfunction
Reproductive system and breast disorders			breast pain, vaginitis	vulvovaginal disorder, uterine cervical disorder, genital discharge
General disorders and administration site conditions		asthenia, oedema peripheral, fatigue, chest pain	pain, thirst, oedema	rigor, pyrexia, influenza like illness, malaise, pelvic pain
Investigations		blood pressure increased	electro-cardiogram abnormal, blood urea increased, blood creatinine increased	blood alkaline phosphatase increased, blood lactase dehydrogenase increased, blood aspartate, aminotransferase increased, blood alanine aminotransferase increased
Injury, poisoning and procedural complications					fall
*Cannot be estimated from the available clinical data.

Undesirable effects noted with other oxybutynin hydrochloride formulations:

In addition, cyclopegia, mydriasis and suppression of lactation have been reported with the use of other oxybutynin hydrochloride formulations.

4.9 Overdose

The symptoms of overdose with oxybutynin progress from an intensification of the usual CNS disturbances (from restlessness and excitement to psychotic behaviour), circulatory changes (flushing, fall in blood pressure, circulatory failure etc.), respiratory failure, paralysis and coma.

Measures to be taken are:

1) administration of activated charcoal

2) physostigmine by slow intravenous injection:

Adults: 0.5 to 2.0 mg i.v. slowly, repeated after 5 minutes if necessary, up to a maximum of 5 mg.

Fever should be treated symptomatically with tepid sponging or ice packs.

In pronounced restlessness or excitation, diazepam 10 mg may be given by intravenous injection. Tachycardia may be treated with intravenous propranolol and urinary retention managed by bladder catheterisation.

In the event of progression of curare-like effects to paralysis of the respiratory muscles, mechanical ventilation will be required.

The continuous release of oxybutynin from Lyrinel XL should be considered in the treatment of overdose. Patients should be monitored for at least 24 hours.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: urinary antispasmodic, ATC code: G04B D04.

Mechanism of action: oxybutynin acts as a competitive antagonist of acetylcholine at post-ganglionic muscarinic receptors, resulting in relaxation of bladder smooth muscle.

Pharmacodynamic effects: in patients with overactive bladder, characterized by detrusor muscle instability or hyperreflexia, cystometric studies have demonstrated that oxybutynin increases maximum urinary bladder capacity and increases the volume to first detrusor contraction. Oxybutynin thus decreases urinary urgency and frequency of both incontinence episodes and voluntary urination.

Oxybutynin is a racemic (50:50) mixture of R- and S- isomers. Antimuscarinic activity resides predominantly in the R-isomer. The R-isomer of oxybutynin shows greater selectivity for the M₁ and M₃ muscarinic subtypes (predominant in bladder detrusor muscle and parotid gland) compared to the M₂ subtype (predominant in cardiac tissue). The active metabolite, N desethyloxybutynin, has pharmacological activity on the human detrusor muscle that is similar to that of oxybutynin in vitro studies, but has a greater binding affinity for parotid tissue than oxybutynin. The free base form of oxybutynin is pharmacologically equivalent to oxybutynin hydrochloride.

Children over the age of 6 years: in children with detrusor hyperreflexia secondary to a neurogenic condition, oxybutynin, in combination with clean intermittent urinary catheterisation, has been shown in open uncontrolled studies to increase mean urine volume per catherisation, increase maximum cystometric capacity and decrease mean detrusor pressure at maximum cystometric capacity.

5.2 Pharmacokinetic Properties

Following the first dose of Lyrinel XL, oxybutynin plasma concentrations rise for 4 to 6 hours; thereafter, concentrations are maintained for up to 24 hours, thus reducing the fluctuations between peak and trough concentrations associated with oxybutynin immediate release formulations.

The relative bioavailabilities of R-oxybutynin and S-oxybutynin from Lyrinel XL are 156% and 187% respectively, compared with oxybutynin immediate release. After a 10 mg single dose of Lyrinel XL, the peak plasma concentrations of R-oxybutynin and S-oxybutynin, achieved after 12.7±5.4 and 11.8±5.3 hours respectively, are 1.0±0.6 and 1.8±1.0 ng/ml, and the plasma concentration time profiles of both enantiomers are similar in shape. The elimination half-life is 13.2±10.3 hours for R-oxybutynin and 12.4±6.1 hours for S-oxybutynin.

Steady state oxybutynin plasma concentrations are achieved by Day 3 of repeated Lyrinel XL dosing, with no observed change in oxybutynin and desethyloxybutynin pharmacokinetic parameters over time.

Pharmacokinetic parameters of oxybutynin and desethyloxybutynin (C_max and AUC) are dose proportional following administration of 5-20 mg of Lyrinel XL.

The pharmacokinetics of Lyrinel XL were similar in all patients studied, irrespective of gender or age and are unaffected by food intake.

Limited data suggest that the pharmacokinetics of Lyrinel XL is similar in adults and children aged 8 years and above. The pharmacokinetics of Lyrinel XL have not been investigated in patients with renal or hepatic insufficiency.

Oxybutynin is extensively metabolised by the liver, primarily by the cytochrome P450 enzyme system, particularly CYP3A4 found mostly in the liver and gut wall. Absolute bioavailability of immediate release oxybutynin has been estimated to be 2-11%. Following intravenous administration of 5 mg oxybutynin, clearance and volume of distribution were estimated to be 26 L/h and 193 L, respectively. Less than 0.1% of the administered dose is excreted unchanged in the urine. Its metabolic products include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and desethyloxybutynin, which is pharmacologically active. Following Lyrinel XL administration, area under the plasma concentration profiles of R- and S-desethyloxybutynin are 73% and 92% respectively of those observed with oxybutynin immediate release formulations.

The binding of oxybutynin to plasma proteins is unknown.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on studies of acute toxicity, repeat dose toxicity, genotoxicity, carcinogenic potential and local toxicity. In a fertility study of subcutaneous oxybutynin injections in rats, female fertility was impaired while no effect was noted in male animals. In a rabbit embryotoxicity study, organ anomalies were observed in the presence of maternal toxicity at a dose of 0.4 mg/kg/day subcutaneously. The relevance to human safety is unknown.

6. Pharmaceutical Particulars

6.1 List Of Excipients

5 mg

Butylhydroxytoluene (E321), cellulose acetate 398-10,, hypromellose 5 cp, macrogol 3350, magnesium stearate, macrogol 200 000, macrogol 2 000 000, sodium chloride, black iron oxide (E172), ferric oxide yellow (E172) and lactose anhydrous.

Film coat: ferric oxide yellow (E172), hypromellose 3 cp and 6 cp, macrogol 400, polysorbate 80 and titanium dioxide (E171).

Printing Ink: black iron oxide (E172), hypromellose 6 cp, propylene glycol and purified water.

10 mg

Butylhydroxytoluene (E321), cellulose acetate 398-10, hypromellose 5 cp, macrogol 3350, magnesium stearate, macrogol 200 000, macrogol 2 000 000, sodium chloride, black iron oxide (E172), ferric oxide red (E172) and lactose anhydrous.

Film coat: ferric oxide red (E172), hypromellose 3 cp and 6 cp, macrogol 400, polysorbate 80 and titanium dioxide (E171).

Printing Ink: black iron oxide (E172), hypromellose 6 cp, propylene glycol and purified water.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Lyrinel XL 5mg: 2 years

Lyrinel XL 10mg: 18 months

6.4 Special Precautions For Storage

Keep the container tightly closed in order to protect from moisture. Do not store above 25^oC.

6.5 Nature And Contents Of Container

High density polyethylene bottles with child resistant closure (polypropylene) and desiccant.

Pack sizes 3, 7, 10, 14, 30, 50, 60, 90 or 100 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Do not remove or swallow the sachet of granules in the bottle. This contains desiccant, which keeps the tablets dry

7. Marketing Authorisation Holder

Janssen-Cilag Limited

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

8. Marketing Authorisation Number(S)

PL 0242/0385

PL 0242/0386

9. Date Of First Authorisation/Renewal Of The Authorisation

1 August 2002/14 June 2010

10. Date Of Revision Of The Text

01 July 2011

Hydrocil

Generic Name: psyllium (SIL ee um)

Brand Names: Fiberall, Hydrocil, Konsyl, Konsyl Orange Sugar-free, Konsyl-D, Konsyl-Orange, Laxmar, Laxmar Orange, Laxmar Sugar Free, Metamucil, Metamucil Berry Burst Smooth Texture Sugar Free, Metamucil Orange Coarse Milled Original Texture, Metamucil Orange Smooth Texture, Metamucil Orange Smooth Texture Sugar Free, Metamucil Original Texture Regular, Metamucil Pink Lemonade Smooth Texture Sugar-Free, Metamucil Unflavored Coarse Milled Original Texture, Metamucil Unflavored Smooth Texture Sugar Free, Natural Fiber Therapy, Perdiem Fiber Powder, Reguloid

What is Hydrocil (psyllium)?

Psyllium is a bulk-forming fiber laxative. Psyllium works by absorbing liquid in the intestines and swelling to create a softer, bulky stool that is easier to pass.

Psyllium is used to treat occasional constipation or bowel irregularity. Psyllium may also be used to treat diarrhea and may help lower cholesterol when used together with a diet low in cholesterol and saturated fat.

Psyllium may also be used for purposes not listed in this product guide.

What is the most important information I should know about Hydrocil (psyllium)?

Laxatives may be habit-forming if they are used too often or for too long. This can lead to damage of intestinal nerves or muscle tissues. Do not take psyllium for longer than directed on the label or prescribed by your doctor. You should not take this product if you are allergic to psyllium, or if you have trouble swallowing, a sudden change in bowel habits that lasts longer than 2 weeks, severe nausea, vomiting, or stomach pain, or if you have ever had a skin rash while taking psyllium.

Also talk with your doctor before using psyllium if you have a colostomy or ileostomy, rectal bleeding, or a blockage in your intestines.

Stop using psyllium and call your doctor at once if you have choking or trouble swallowing, severe stomach pain or cramping, nausea or vomiting, constipation that lasts longer than 7 days, rectal bleeding, or itchy skin rash. Do not take psyllium for longer than 7 days in a row unless your doctor has told you to.

What should I discuss with my healthcare provider before taking Hydrocil (psyllium)?

Laxatives may be habit-forming if they are used too often or for too long. This can lead to damage of intestinal nerves or muscle tissues. Do not take psyllium for longer than directed on the label or prescribed by your doctor. You should not take this product if you are allergic to psyllium, or if you have:

• 
  

  trouble swallowing;

  
  


• 
  

  a sudden change in bowel habits that lasts longer than 2 weeks;

  
  


• 
  

  severe nausea, vomiting, or stomach pain; or

  
  


• 
  

  if you have ever had a skin rash while taking psyllium.

  
  

Ask a doctor or pharmacist if it is safe for you to take this medicine if you have:

• 
  

  a colostomy or ileostomy;

  
  


• 
  

  rectal bleeding; or

  
  


• 
  

  a blockage in your intestines.

  
  

Psyllium products may contain sugar, sodium, or artificial sweeteners. This may be of concern to you if you have diabetes, high blood pressure, or phenylketonuria (PKU). Check the product label if you have any of these conditions.

Psyllium is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether psyllium passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take Hydrocil (psyllium)?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended.

Take psyllium with a full glass (at least 8 ounces) of water or another liquid. Taking psyllium without enough liquid may cause it to swell in your throat and cause choking. Drinking plenty of fluids each day while you are taking psyllium will also help improve bowel regularity.

The psyllium wafer must be chewed before you swallow it.

Do not swallow psyllium powder dry. It must be mixed with liquid. Place the psyllium powder into an empty glass and add at least 8 ounces of water or other liquid such as fruit juice. Stir this mixture and drink all of it right away.

If the powder and liquid mixture is too thick, add more liquid. After drinking the entire mixture, add a little more liquid to the same glass, swirl gently and drink right away to make sure you get the entire dose of psyllium.

Psyllium may be only part of a complete program of treatment that also includes diet, exercise, and weight control. Follow your diet, medication, and exercise routines very closely.

It may take up to 3 days of using this medicine before your symptoms improve. For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve after 2 or 3 days of treatment.

Do not take psyllium for longer than 7 days in a row unless your doctor has told you to. Store at room temperature away from moisture and heat.

What happens if I miss a dose?

Since psyllium is used as needed, it does not have a daily dosing schedule. Call your doctor promptly if your symptoms do not improve after using psyllium.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include nausea, vomiting, and stomach pain. Using a laxative too often or for too long may cause severe medical problems involving your intestines.

What should I avoid while taking Hydrocil (psyllium)?

Avoid taking other oral (by mouth) medications within 2 hours before or after you take psyllium. Bulk-forming laxatives can make it harder for your body to absorb other medications, possibly making them less effective.

Avoid breathing in the dust from psyllium powder when mixing. Inhaling psyllium dust may cause an allergic reaction.

If you take psyllium as part of a cholesterol-lowering treatment plan, avoid eating foods that are high in fat or cholesterol. Your treatment will not be as effective in lowering your cholesterol if you do not follow a cholesterol-lowering diet plan.

Hydrocil (psyllium) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using psyllium and call your doctor at once if you have a serious side effect such as:

• 
  

  choking or trouble swallowing;

  
  


• 
  

  severe stomach pain, cramping, nausea or vomiting;

  
  


• 
  

  constipation that lasts longer than 7 days;

  
  


• 
  

  rectal bleeding; or

  
  


• 
  

  itchy skin rash.

  
  

Less serious side effects may include:

• 
  

  bloating; or

  
  


• 
  

  minor change in your bowel habits.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Hydrocil (psyllium)?

Tell your doctor about all other medications you use, especially:

• 
  

  a blood thinner such as warfarin (Coumadin, Jantoven); or

  
  


• 
  

  demeclocycline (Declomycin), doxycycline (Adoxa, Doryx, Oracea, Vibramycin), minocycline (Dynacin, Minocin, Solodyn, Vectrin), or tetracycline (Brodspec, Panmycin, Sumycin, Tetracap).

  
  

This list is not complete and other drugs may interact with psyllium. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Hydrocil resources

• Hydrocil Side Effects (in more detail)
• Hydrocil Use in Pregnancy & Breastfeeding
• Hydrocil Drug Interactions
• Hydrocil Support Group
• 0 Reviews for Hydrocil - Add your own review/rating

• Konsyl Powder MedFacts Consumer Leaflet (Wolters Kluwer)


• Metamucil MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Hydrocil with other medications

• Constipation
• Dietary Fiber Supplementation
• Irritable Bowel Syndrome

Where can I get more information?

• Your pharmacist can provide more information about psyllium.

See also: Hydrocil side effects (in more detail)

Kytril Ampoules 1mg / 1ml

1. Name Of The Medicinal Product

Kytril Ampoules 1mg/1ml

2. Qualitative And Quantitative Composition

Each 1ml contains 1mg granisetron (as the hydrochloride). For excipients, see section 6.1.

3. Pharmaceutical Form

A glass ampoule containing a sterile, clear colourless solution. The content allows withdrawal of 1ml.

Concentrate for solution for infusion or injection.

4. Clinical Particulars

4.1 Therapeutic Indications

Kytril is indicated for the prevention or treatment of nausea and vomiting induced by cytostatic therapy and for the prevention and treatment of post-operative nausea and vomiting.

4.2 Posology And Method Of Administration

Cytostatic therapy

Children

Prevention: A single dose of 40μg/kg bodyweight (up to 3mg) should be administered as an intravenous infusion, diluted in 10 to 30ml infusion fluid and administered over five minutes. Administration should be completed prior to the start of cytostatic therapy.

Treatment: The same dose of Kytril as above should be used for treatment as prevention.

One additional dose of 40μg/kg bodyweight (up to 3mg) may be administered within a 24-hour period if required. This additional dose should be administered at least 10 minutes apart from the initial infusion.

Renally impaired

No special requirements apply.

Hepatically impaired

No special requirements apply.

Post-operative nausea and vomiting

Adults

For prevention in adults, a single dose of 1mg of Kytril should be diluted to 5ml and administered as a slow intravenous injection (over 30 seconds). Administration should be completed prior to induction of anaesthesia.

For the treatment of established post-operative nausea and vomiting in adults, a single dose of 1mg of Kytril should be diluted to 5ml and administered by slow intravenous injection (over 30 seconds).

Maximum dose and duration of treatment

Two doses (2mg) in one day.

Children

There is no experience in the use of Kytril in the prevention and treatment of post-operative nausea and vomiting in children. Kytril is not therefore recommended for the treatment of post-operative nausea and vomiting in this age group.

Elderly

As for adults.

Renally impaired

As for adults.

Hepatically impaired

As for adults.

4.3 Contraindications

Hypersensitivity to granisetron or related substances.

4.4 Special Warnings And Precautions For Use

As Kytril may reduce lower bowel motility, patients with signs of sub-acute intestinal obstruction should be monitored following administration of Kytril.

No special precautions are required for the elderly or renally or hepatically impaired patient.

As for other 5-HT₃ antagonists, cases of ECG modifications including QT prolongation have been reported with Kytril. These ECG changes with Kytril were minor and generally not of clinical significance, specifically with no evidence of proarrhythmia. However, in patients with pre-existing arrhythmias or cardiac conduction disorders, this might lead to clinical consequences. Therefore, caution should be exercised in patients with cardiac co-morbidities, on cardio-toxic chemotherapy and/or with concomitant electrolyte abnormalities.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In studies in healthy subjects, no evidence of any interaction has been indicated between Kytril and cimetidine or lorazepam. No evidence of drug interactions has been observed in clinical studies conducted.

No specific interaction studies have been conducted in anaesthetised patients, but Kytril has been safely administered with commonly used anaesthetic and analgesic agents. In addition, in vitro human microsomal studies have shown that the cytochrome P450 sub-family 3A4 (involved in the metabolism of some of the main narcotic analgesic agents) is not modified by Kytril.

As for other 5-HT₃ antagonists, cases of ECG modifications including QT prolongation have been reported with Kytril. These ECG changes with Kytril were minor and generally not of clinical significance, specifically with no evidence of proarrhythmia. However, in patients concurrently treated with drugs known to prolong QT interval and/or are arrhythmogenic, this may lead to clinical consequences.

4.6 Pregnancy And Lactation

Whilst animal studies have shown no teratogenic effects, there is no experience of Kytril in human pregnancy. Therefore Kytril should not be administered to women who are pregnant unless there are compelling clinical reasons. There are no data on the excretion of Kytril in breast milk. Breast feeding should therefore be discontinued during therapy.

4.7 Effects On Ability To Drive And Use Machines

There has been no evidence from human studies that Kytril has any adverse effect on alertness.

4.8 Undesirable Effects

Kytril has been generally well tolerated in human studies. As reported with other drugs of this class, headache and constipation have been the most frequently noted adverse events but the majority have been mild or moderate in nature. Rare cases of hypersensitivity reaction, occasionally severe (e.g. anaphylaxis) have been reported. Other allergic reactions including minor skin rashes have also been reported. In clinical trials, transient increases in hepatic transaminases, generally within the normal range, have been seen.

Dystonias and dyskinesias have been reported with medicines in the 5-HT₃ antagonist class. Such events have been reported rarely with Kytril.

As for other 5-HT₃ antagonists, cases of ECG modifications including QT prolongation have been reported with Kytril. These ECG changes with Kytril were minor and generally not of clinical significance, specifically with no evidence of proarrhythmia. (See section 4.4 Special Warnings and Precautions for Use and 4.5 Interactions with other Medicinal Products and other Forms of Interaction)

4.9 Overdose

There is no specific antidote for Kytril. In the case of overdosage, symptomatic treatment should be given. One patient has received 30mg of Kytril intravenously. The patient reported a slight headache but no other sequelae were observed.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Kytril is a potent anti-emetic and highly selective antagonist of 5-hydroxytryptamine (5₃) receptors. Radioligand binding studies have demonstrated that Kytril has negligible affinity for other receptor types including 5₂ binding sites.

Kytril is effective intravenously, either prophylactically or by intervention, in abolishing the retching and vomiting evoked by administration of cytotoxic drugs or by whole body X

Kytril is effective, intravenously, in the prevention and treatment of post-operative nausea and vomiting.

5.2 Pharmacokinetic Properties

General characteristics

Distribution

Kytril is extensively distributed, with a mean volume of distribution of approximately 3L/kg; plasma protein binding is approximately 65%.

Biotransformation

Biotransformation pathways involve N-demethylation and aromatic ring oxidation followed by conjugation.

Elimination

Clearance is predominantly by hepatic metabolism. Urinary excretion of unchanged Kytril averages 12% of dose whilst that of metabolites amounts to about 47% of dose. The remainder is excreted in faeces as metabolites. Mean plasma half-life in patients is approximately nine hours, with a wide inter-subject variability.

Characteristics in patients

The plasma concentration of Kytril is not clearly correlated with anti-emetic efficacy. Clinical benefit may be conferred even when Kytril is not detectable in plasma.

In elderly subjects after single intravenous doses, pharmacokinetic parameters were within the range found for non-elderly subjects. In patients with severe renal failure, data indicate that pharmacokinetic parameters after a single intravenous dose are generally similar to those in normal subjects. In patients with hepatic impairment due to neoplastic liver involvement, total plasma clearance of an intravenous dose was approximately halved compared to patients without hepatic involvement. Despite these changes, no dosage adjustment is necessary.

5.3 Preclinical Safety Data

Data from two-year carcinogenicity studies have shown an increase in hepatocellular carcinoma and/or adenoma in rats and mice of both sexes given 50mg/kg (rat dosage reduced to 25mg/kg/day at week 59). Increases in hepatocellular neoplasia were also detected at 5mg/kg in male rats. In both species, drug-induced effects (hepatocellular neoplasia) were not observed in the low-dose group (1mg/kg).

In several in vitro and in vivo assays, Kytril was shown to be non-genotoxic in mammalian cells.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Chloride

Water for Injection

Citric acid, monohydrate

Hydrochloric acid

Sodium hydroxide

6.2 Incompatibilities

As a general precaution, Kytril should not be mixed in solution with other drugs. Prophylactic administration of Kytril should be completed prior to the start of cytostatic therapy or induction of anaesthesia.

6.3 Shelf Life

Kytril ampoules have a shelf-life of three years.

Once opened 24 hours.

6.4 Special Precautions For Storage

Do not store above 30°C. Keep container in the outer carton. Do not freeze.

6.5 Nature And Contents Of Container

Kytril is supplied in clear glass ampoules in packs of five, with an outer carton.

6.6 Special Precautions For Disposal And Other Handling

Preparing the infusion

Children: To prepare the dose of 40 μg/kg, the appropriate volume is withdrawn and diluted with infusion fluid to a total volume of 10 to 30ml. Any one of the following solutions may be used: 0.9% w/v Sodium Chloride Injection BP; 0.18% w/v Sodium Chloride and 4% w/v Glucose Injection BP; 5% w/v Glucose Injection BP; Hartmann's Solution for Injection BP; Sodium Lactate Injection BP; or 10% Mannitol Injection BP. No other diluents should be used.

Ideally, intravenous infusions of Kytril should be prepared at the time of administration. After dilution (see above), or when the container is opened for the first time, the shelf-life is 24 hours when stored at ambient temperature in normal indoor illumination protected from direct sunlight. It must not be used after 24 hours. If to be stored after preparation, Kytril infusions must be prepared under appropriate aseptic conditions.

Adults: to prepare a dose of 1mg, 1ml should be withdrawn from the ampoule and diluted to 5ml with 0.9% w/v Sodium Chloride Injection BP. No other diluent should be used.

7. Marketing Authorisation Holder

Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom.

8. Marketing Authorisation Number(S)

PL 00031/0595

9. Date Of First Authorisation/Renewal Of The Authorisation

23^rd October 1995/23^rd October 2000.

10. Date Of Revision Of The Text

23 December 2009

LEGAL STATUS

POM

Kytril is a registered trade mark

Item Code

nimodipine

Generic Name: nimodipine (nih MO dih peen)

Brand Names: Nimotop

What is nimodipine?

Nimodipine is in a group of drugs called calcium channel blockers. Nimodipine relaxes (widens) blood vessels and improves blood flow.

Nimodipine is used to prevent brain damage caused by reduced blood flow to the brain resulting from aneurysm (AN-yor-iz-m), a dilated or ruptured blood vessel in the brain.

Nimodipine may also be used for purposes other than those listed here.

What is the most important information I should know about nimodipine?

Before taking nimodipine, tell your doctor if you have liver disease, low blood pressure, high blood pressure (hypertension) for which you take medicine, or a history of heart problems such as a slow heart rate, congestive heart failure, or heart attack.

Nimodipine gel capsules are to be taken by mouth only. The medicine in the capsule should never be placed into a needle and syringe and injected into a vein. If the person taking nimodipine cannot swallow the capsule, use a needle to make a hole in each end of the capsule, and squeeze the medicine out into an oral syringe. The syringe can then be used to give the medicine through a nasogastric (through the nose and into the stomach) tube.

If you are able to swallow capsules, take nimodipine on an empty stomach, one hour before or two hours after meals. Avoid drinking alcohol while you are taking nimodipine. Alcohol and nimodipine may cause low blood pressure, drowsiness, or dizziness. Do not stop taking nimodipine without first talking to your doctor, even if you begin to feel better. If you stop taking the medication, your condition could become worse.

What should I discuss with my healthcare provider before taking nimodipine?

Before taking nimodipine, tell your doctor if you have:

• liver disease;


• 
  

  low blood pressure;

  
  


• 
  

  high blood pressure for which you take medication; or

  
  


• 
  

  a history of heart problems such as a slow heart rate, congestive heart failure, or heart attack.

  
  

If you have any of these conditions, you may not be able to use nimodipine, or you may need a dosage adjustment or special tests during treatment.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known if nimodipine passes into breast milk or if it could harm a nursing infant. Do not take nimodipine without telling your doctor if you are breast-feeding a baby. If you are over 65 years of age, you may be more likely to have side effects from nimodipine. Your doctor may prescribe a lower dose of this medication.

How should I take nimodipine?

Take nimodipine exactly as it was prescribed for you. Do not take it in larger doses or for longer than recommended by your doctor.

Nimodipine gel capsules are to be taken by mouth only. The medicine in the capsule should never be placed into a needle and syringe and injected into a vein. If the person taking nimodipine cannot swallow the capsule, use a needle to make a hole in each end of the capsule, and squeeze the medicine out into an oral syringe. The syringe can then be used to give the medicine through a nasogastric (through the nose and into the stomach) tube.

If you are able to swallow capsules, take nimodipine on an empty stomach, one hour before or two hours after meals. Take each dose with a full glass of water.

It is important to take nimodipine regularly to get the most benefit.

Do not stop taking nimodipine without first talking to your doctor, even if you begin to feel better. If you stop taking the medication, your condition could become worse.

To be sure this medication is helping your condition, your blood pressure will need to be tested on a regular basis. Your liver function may also need to be tested. It is important that you not miss any scheduled visits to your doctor.

Store nimodipine at room temperature away from moisture and heat.

See also: Nimodipine dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Symptoms of a nimodipine overdose may include dizziness, weakness, chest pain, shortness of breath, fainting, an unusually fast or slow heartbeat, slurred speech, confusion, or coma.

What should I avoid while taking nimodipine?

Avoid drinking alcohol while you are taking nimodipine. Alcohol and nimodipine may cause low blood pressure, drowsiness, or dizziness.

Nimodipine side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using nimodipine and call your doctor at once if you have any of these serious side effects:

• 
  

  unusually fast or slow heartbeats;

  
  


• 
  

  fainting or severe dizziness;

  
  


• 
  

  easy bruising or bleeding, unusual weakness;

  
  


• 
  

  swelling in your legs or ankles.

  
  

Other, less serious side effects may be more likely. Continue taking nimodipine and talk to your doctor if you have any of these less serious side effects:

• 
  

  mild dizziness;

  
  


• 
  

  flushing (redness, warmth, or tingling feeling);

  
  


• 
  

  headache;

  
  


• 
  

  nausea, constipation; or

  
  


• 
  

  sweating.

  
  

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

Nimodipine Dosing Information

Usual Adult Dose for Subarachnoid Hemorrhage:

60 mg orally every 4 hours
Therapy should be started within 96 hours of the event and continued for 21 days.

Usual Adult Dose for Ischemic Stroke:

(Not approved by FDA)

30 mg orally every 6 hours
Therapy should be started within 24 hours of the event and continued for 28 days.

Usual Adult Dose for Migraine Prophylaxis:

(Not approved by FDA)

30 mg orally every 6 hours

What other drugs will affect nimodipine?

There may be other drugs that can affect nimodipine, resulting in side effects and/or reduced effectiveness. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More nimodipine resources

• Nimodipine Side Effects (in more detail)
• Nimodipine Dosage
• Nimodipine Use in Pregnancy & Breastfeeding
• Drug Images
• Nimodipine Drug Interactions
• Nimodipine Support Group
• 2 Reviews for Nimodipine - Add your own review/rating

• nimodipine Advanced Consumer (Micromedex) - Includes Dosage Information


• Nimodipine Prescribing Information (FDA)


• Nimodipine Professional Patient Advice (Wolters Kluwer)


• Nimodipine Monograph (AHFS DI)


• Nimodipine MedFacts Consumer Leaflet (Wolters Kluwer)


• Nimotop Prescribing Information (FDA)

Compare nimodipine with other medications

• Ischemic Stroke
• Migraine Prevention
• Subarachnoid Hemorrhage

Where can I get more information?

• Your pharmacist has additional information about nimodipine written for health professionals that you may read.

See also: nimodipine side effects (in more detail)