Search Articles Directory United States of America: September 2012

Saturday 29 September 2012

Exemestane 25mg Film-coated Tablets (Actavis UK Ltd)

1. Name Of The Medicinal Product

Exemestane 25mg Film-coated Tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 25 mg exemestane.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

Exemestane 25 mg film-coated tablets are white, round, lenticular, with uniform appearance and intact edges.

4. Clinical Particulars

4.1 Therapeutic Indications

Adjuvant treatment of postmenopausal women with oestrogen receptor positive invasive early breast cancer, following 2-3 years of initial adjuvant tamoxifen therapy.

Treatment of advanced breast cancer in women with natural or induced postmenopausal status whose disease has progressed following anti-oestrogen therapy. Efficacy has not been demonstrated in patients with oestrogen receptor negative status.

4.2 Posology And Method Of Administration

Adult and elderly patients

The recommended dose of Exemestane 25mg Film-coated Tablets is one 25 mg tablet to be taken once daily, after a meal.

In patients with early breast cancer, treatment with Exemestane 25mg Film-coated Tablets should continue until completion of five years of combined sequential adjuvant hormonal therapy (tamoxifen followed by Exemestane 25mg Film-coated Tablets), or earlier if tumour relapse occurs.

In patients with advanced breast cancer, treatment with Exemestane 25mg Film-coated Tablets should continue until tumour progression is evident.

No dose adjustments are required for patients with hepatic or renal insufficiency (see section 5.2).

Children

Exemestane 25mg Film-coated Tablets is not recommended for use in children.

4.3 Contraindications

Known hypersensitivity to the active substance or to any of the excipients.

Pre-menopausal women and pregnant or lactating women.

4.4 Special Warnings And Precautions For Use

Exemestane should not be administered to women with pre-menopausal endocrine status. Therefore, whenever clinically appropriate, the post-menopausal status should be ascertained by assessment of LH, FSH and oestradiol levels.

Exemestane should be used with caution in patients with hepatic or renal impairment.

Exemestane is a potent oestrogen lowering agent, and a reduction in bone mineral density and an increased fracture rate has been observed following administration (see section 5.1). During adjuvant treatment with exemestane, women with osteoporosis or at risk of osteoporosis should have their bone mineral density formally assessed by bone densitometry at the commencement of treatment. Although adequate data to show the effects of therapy in the treatment of the bone mineral density loss caused by exemestane are not available, treatment for osteoporosis should be initiated in at risk patients. Patients treated with Exemestane 25mg Film-coated Tablets should be carefully monitored.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In vitro evidence showed that the drug is metabolised through cytochrome P450 (CYP) 3A4 and aldoketoreductases (see section 5.2) and does not inhibit any of the major CYP isoenzymes. In a clinical pharmacokinetic study, the specific inhibition of CYP 3A4 by ketoconazole showed no significant effects on the pharmacokinetics of exemestane.

In an interaction study with rifampicin, a potent CYP450 inducer, at a dose of 600 mg daily and a single dose of exemestane 25 mg, the AUC of exemestane was reduced by 54% and C_max by 41%. Since the clinical relevance of this interaction has not been evaluated, the co-administration of drugs, such as rifampicin, anticonvulsants (e.g. phenytoin and carbamazepine) and herbal preparations containing Hypericum perforatum (St John's Wort) known to induce CYP3A4 may reduce the efficacy of exemestane.

Exemestane should be used cautiously with drugs that are metabolised via CYP3A4 and have a narrow therapeutic window. There is no clinical experience of the concomitant use of exemestane with other anticancer drugs.

Exemestane should not be coadministered with oestrogen-containing medicines as these would negate its pharmacological action.

4.6 Pregnancy And Lactation

Pregnancy

No clinical data on exposed pregnancies are available with exemestane. Studies on animals have shown reproductive toxicity (see section 5.3). Exemestane 25mg Film-coated Tablets is therefore contraindicated in pregnant women.

Lactation

It is not known whether exemestane is excreted into human milk. Exemestane 25mg Film-coated Tablets should not be administered to lactating woman.

Women of perimenopausal status or child-bearing potential

The physician needs to discuss the necessity of adequate contraception with women who have the potential to become pregnant including women who are perimenopausal or who have recently become postmenopausal, until their postmenopausal status is fully established (see section 4.3 and section 4.4).

4.7 Effects On Ability To Drive And Use Machines

Drowsiness, somnolence, asthenia and dizziness have been reported with the use of the drug. Patients should be advised that, if these events occur, their physical and/or mental abilities required for operating machinery or driving a car may be impaired.

4.8 Undesirable Effects

Exemestane was generally well tolerated across all clinical studies conducted with exemestane at a standard dose of 25 mg/day, and undesirable effects were usually mild to moderate.

The withdrawal rate due to adverse events was 7.4% in patients with early breast cancer receiving adjuvant treatment with exemestane following initial adjuvant tamoxifen therapy. The most commonly reported adverse reactions were hot flushes (22%), arthralgia (18%) and fatigue (16%).

The withdrawal rate due to adverse events was 2.8% in the overall patient population with advanced breast cancer. The most commonly reported adverse reactions were hot flushes (14%) and nausea (12%).

Most adverse reactions can be attributed to the normal pharmacological consequences of oestrogen deprivation (e.g. hot flushes).

The reported adverse reactions are listed below by system organ class and by frequency.

Frequencies are defined as:

Very common (

Common (

Uncommon (

Rare (

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

Metabolism and nutrition disorders:
Common	Anorexia
Psychiatric disorders:
Very common	Insomnia
Common	Depression
Nervous system disorders:
Very common	Headache
Common	Dizziness, carpal tunnel syndrome
Uncommon	Somnolence
Vascular disorders:
Very common	Hot flushes
Gastrointestinal disorders:
Very common	Nausea
Common	Abdominal pain, vomiting, constipation, dyspepsia, diarrhoea
Skin and subcutaneous tissue disorders:
Very common	Increased sweating
Common	Rash, alopecia
Musculoskeletal and bone disorders:
Very common	Joint and musculoskeletal pain (Includes: arthralgia, and less frequently pain in limb, osteoarthritis, back pain, arthritis, myalgia and joint stiffness)
Common	Osteoporosis, fracture
General disorders and administration site conditions:
Very common	Fatigue
Common	Pain, peripheral oedema
Uncommon	Asthenia
Blood and lymphatic system disorders

In patients with advanced breast cancer thrombocytopenia and leucopenia have been rarely reported. An occasional decrease in lymphocytes has been observed in approximately 20% of patients receiving exemestane, particularly in patients with pre-existing lymphopenia; however, mean lymphocyte values in these patients did not change significantly over time and no corresponding increase in viral infections was observed. These effects have not been observed in patients treated in early breast cancer studies.

Hepatobiliary disorders

Elevation of liver function test parameters including enzymes, bilirubin and alkaline phosphatase have been observed.

The table below presents the frequency of pre-specified adverse events and illnesses in the early breast cancer study (IES), irrespective of causality, reported in patients receiving trial therapy and up to 30 days after cessation of trial therapy.

Adverse events and illnesses	Exemestane (N = 2249)	Tamoxifen (N = 2279)
Hot flushes	491 (21.8%)	457 (20.1%)
Fatigue	367 (16.3%)	344 (15.1%)
Headache	305 (13.6%)	255 (11.2%)
Insomnia	290 (12.9%)	204 (9.0%)
Sweating increased	270 (12.0%)	242 (10.6%)
Gynaecological	235 (10.5%)	340 (14.9%)
Dizziness	224 (10.0%)	200 (8.8%)
Nausea	200 (8.9%)	208 (9.1%)
Osteoporosis	116 (5.2%)	66 (2.9%)
Vaginal haemorrhage	90 (4.0%)	121 (5.3%)
Other primary cancer	84 (3.6%)	125 (5.3%)
Vomiting	50 (2.2%)	54 (2.4%)
Visual disturbance	45 (2.0%)	53 (2.3%)
Thromboembolism	16 (0.7%)	42 (1.8%)
Osteoporotic fracture	14 (0.6%)	12 (0.5%)
Myocardial infarction	13 (0.6%)	4 (0.2%)

In the IES study, the frequency of ischemic cardiac events in the exemestane and tamoxifen treatment arms was 4.5% versus 4.2%, respectively. No significant difference was noted for any individual cardiovascular event including hypertension (9.9% versus 8.4%), myocardial infarction (0.6% versus 0.2%) and cardiac failure (1.1% versus 0.7%).

In the IES study, exemestane was associated with a greater incidence of hypercholesterolemia compared with tamoxifen (3.7% vs. 2.1%).

In a separate double blinded, randomized study of postmenopausal women with early breast cancer at low risk treated with exemestane (N=73) or placebo (N=73) for 24 months , exemestane was associated with an average 7-9% mean reduction in plasma HDL-cholesterol, versus a 1% increase on placebo. There was also a 5-6% reduction in apolipoprotein A1 in the exemestane group versus 0-2% for placebo. The effect on the other lipid parameters analysed (total cholesterol, LDL cholesterol, triglycerides, apolipoprotein-B and lipoprotein-a) was very similar in the two treatment groups . The clinical significance of these results is unclear.

In the IES study, gastric ulcer was observed at a higher frequency in the exemestane arm compared to tamoxifen (0.7% versus <0.1%). The majority of patients on exemestane with gastric ulcer received concomitant treatment with non-steroidal anti-inflammatory agents and/or had a prior history.

Adverse reactions from post-marketing experience

Hepatobiliary disorders: Hepatitis, cholestatic hepatitis.

Because reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

4.9 Overdose

Clinical trials have been conducted with exemestane given up to 800 mg in a single dose to healthy female volunteers and up to 600 mg daily to postmenopausal women with advanced breast cancer; these dosages were well tolerated. The single dose of exemestane that could result in life-threatening symptoms is not known. In rats and dogs, lethality was observed after single oral doses equivalent respectively to 2000 and 4000 times the recommended human dose on a mg/m² basis. There is no specific antidote to overdosage and treatment must be symptomatic. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Hormone antagonists and related agents; enzyme inhibitors. ATC code: L02BG06

Exemestane is an irreversible, steroidal aromatase inhibitor, structurally related to the natural substrate androstenedione. In post-menopausal women, oestrogens are produced primarily from the conversion of androgens into oestrogens through the aromatase enzyme in peripheral tissues. Oestrogen deprivation through aromatase inhibition is an effective and selective treatment for hormone dependent breast cancer in postmenopausal women. In postmenopausal women, exemestane p.o. significantly lowered serum oestrogen concentrations starting from a 5 mg dose, reaching maximal suppression (>90%) with a dose of 10-25 mg. In postmenopausal breast cancer patients treated with the 25 mg daily dose, whole body aromatization was reduced by 98%.

Exemestane does not possess any progestogenic or oestrogenic activity. A slight androgenic activity, probably due to the 17-hydro derivative, has been observed mainly at high doses. In multiple daily doses trials, exemestane had no detectable effects on adrenal biosynthesis of cortisol or aldosterone, measured before or after ACTH challenge, thus demonstrating its selectivity with regard to the other enzymes involved in the steroidogenic pathway.

Glucocorticoid or mineralocorticoid replacements are therefore not needed. A non dose-dependent slight increase in serum LH and FSH levels has been observed even at low doses: this effect is, however, expected for the pharmacological class and is probably the result of feedback at the pituitary level due to the reduction in oestrogen levels that stimulate the pituitary secretion of gonadotropins also in postmenopausal women.

Adjuvant Treatment of Early Breast Cancer

In a multicentre, randomised, double-blind study, conducted in 4724 postmenopausal patients with oestrogen-receptor-positive or unknown primary breast cancer, patients who had remained disease-free after receiving adjuvant tamoxifen therapy for 2 to 3 years were randomised to receive 3 to 2 years of exemestane (25 mg/day) or tamoxifen (20 or 30 mg/day) to complete a total of 5 years of hormonal therapy.

After a median duration of therapy of about 30 months and a median follow-up of about 52 months, results showed that sequential treatment with exemestane after 2 to 3 years of adjuvant tamoxifen therapy was associated with a clinically and statistically significant improvement in disease-free survival (DFS) compared with continuation of tamoxifen therapy. Analysis showed that in the observed study period exemestane reduced the risk of breast cancer recurrence by 24% compared with tamoxifen (hazard ratio 0.76; p=0.00015). The beneficial effect of exemestane over tamoxifen with respect to DFS was apparent regardless of nodal status or prior chemotherapy.

Exemestane also significantly reduced the risk of contralateral breast cancer (hazard ratio 0.57, p=0.04158).

In the whole study population, a trend for improved overall survival was observed for exemestane (222 deaths) compared to tamoxifen (262 deaths) with a hazard ratio 0.85 (log-rank test: p = 0.07362), representing a 15% reduction in the risk of death in favor of exemestane. A statistically significant 23% reduction in the risk of dying (hazard ratio for overall survival 0.77; Wald chi square test: p = 0.0069) was observed for exemestane compared to tamoxifen when adjusting for the pre-specified prognostic factors (i.e., ER status, nodal status, prior chemotherapy, use of HRT and use of bisphosphonates).

Main efficacy results in all patients (intention to treat population) and oestrogen receptor positive patients are summarised in the table below:

Endpoint Population	Exemestane Events /N (%)	Tamoxifen Events /N (%)	Hazard Ratio (95% CI)	p-value*
Disease-free survival ^a
All patients	354 /2352 (15.1%)	453 /2372 (19.1%)	0.76 (0.67-0.88)	0.00015
ER+ patients	289 /2023 (14.3%)	370 /2021 (18.3%)	0.75 (0.65-0.88)	0.00030
Contralateral breast cancer
All patients	20 /2352 (0.9%)	35 /2372 (1.5%)	0.57 (0.33-0.99)	0.04158
ER+ patients	18 /2023 (0.9%)	33 /2021 (1.6%)	0.54 (0.30-0.95)	0.03048
Breast cancer free survival ^b
All patients	289 /2352 (12.3%)	373 /2372 (15.7%)	0.76 (0.65-0.89)	0.00041
ER+ patients	232 /2023 (11.5%)	305 /2021 (15.1%)	0.73 (0.62-0.87)	0.00038
Distant recurrence free survival ^c
All patients	248 /2352 (10.5%)	297 /2372 (12.5%)	0.83 (0.70-0.98)	0.02621
ER+ patients	194 /2023 (9.6%)	242 /2021 (12.0%)	0.78 (0.65-0.95)	0.01123
Overall survival ^d
All patients	222 /2352 (9.4%)	262 /2372 (11.0%)	0.85 (0.71-1.02)	0.07362
ER+ patients	178 /2023 (8.8%)	211 /2021 (10.4%)	0.84 (0.68-1.02)	0.07569

* Log-rank test; ER+ patients = oestrogen receptor positive patients;

^a Disease-free survival is defined as the first occurrence of local or distant recurrence, contralateral breast cancer, or death from any cause;

^b Breast cancer free survival is defined as the first occurrence of local or distant recurrence, contralateral breast cancer or breast cancer death;

^c Distant recurrence free survival is defined as the first occurrence of distant recurrence or breast cancer death;

^d Overall survival is defined as occurrence of death from any cause.

In the additional analysis for the subset of patients with oestrogen receptor positive or unknown status, the unadjusted overall survival hazard ratio was 0.83 (log-rank test: p = 0.04250), representing a clinically and statistically significant 17% reduction in the risk of dying.

Results from a bone substudy demonstrated that women treated with exemestane following 2 to 3 years of tamoxifen treatment experienced moderate reduction in bone mineral density. In the overall study, the treatment emergent fracture incidence evaluated during the 30 months treatment period was higher in patients treated with exemestane compared with tamoxifen (4.5% and 3.3% correspondingly, p = 0.038).

Results from an endometrial substudy indicate that after 2 years of treatment there was a median 33% reduction of endometrial thickness in the exemestane -treated patients compared with no notable variation in the tamoxifen-treated patients. Endometrial thickening, reported at the start of study treatment, was reversed to normal (< 5 mm) for 54% of patients treated with exemestane.

Treatment of Advanced Breast Cancer

In a randomised peer reviewed controlled clinical trial, exemestane at the daily dose of 25 mg has demonstrated statistically significant prolongation of survival, Time to Progression (TTP), Time to Treatment Failure (TTF) as compared to a standard hormonal treatment with megestrol acetate in postmenopausal patients with advanced breast cancer that had progressed following, or during, treatment with tamoxifen either as adjuvant therapy or as first-line treatment for advanced disease.

5.2 Pharmacokinetic Properties

Absorption

After oral administration, exemestane is absorbed rapidly. The fraction of the dose absorbed from the gastrointestinal tract is high. The absolute bioavailability in humans is unknown, although it is anticipated to be limited by an extensive first pass effect. A similar effect resulted in an absolute bioavailability in rats and dogs of 5%. After a single dose of 25 mg, maximum plasma levels of 18 ng/ml are reached after 2 hours. Concomitant intake with food increases the bioavailability by 40%.

Distribution

The volume of distribution of exemestane, not corrected for the oral bioavailability, is ca 20,000 l. The kinetics is linear and the terminal elimination half-life is 24 h. Binding to plasma proteins is 90% and is concentration independent. Exemestane and its metabolites do not bind to red blood cells.

Exemestane does not accumulate in an unexpected way after repeated dosing.

Metabolism and excretion

Exemestane is metabolised by oxidation of the methylene moiety on the 6 position by CYP 3A4 isoenzyme and/or reduction of the 17-keto group by aldoketoreductase followed by conjugation. The clearance of exemestane is ca 500 l/h, not corrected for the oral bioavailability.

The metabolites are inactive or the inhibition of aromatase is less than the parent compound.

The amount excreted unchanged in urine is 1% of the dose. In urine and faeces equal amounts (40%) of ¹⁴C-labeled exemestane were eliminated within a week.

Special populations

Age

No significant correlation between the systemic exposure of exemestane and the age of subjects has been observed.

Renal insufficiency

In patients with severe renal impairment (CL_cr < 30 ml/min) the systemic exposure to exemestane was 2 times higher compared with healthy volunteers.

Given the safety profile of exemestane, no dose adjustment is considered to be necessary.

Hepatic insufficiency

In patients with moderate or severe hepatic impairment the exposure of exemestane is 2-3 fold higher compared with healthy volunteers. Given the safety profile of exemestane, no dose adjustment is considered to be necessary.

5.3 Preclinical Safety Data

Toxicological studies

Findings in the repeat dose toxicology studies in rat and dog were generally attributable to the pharmacological activity of exemestane, such as effects on reproductive and accessory organs. Other toxicological effects (on liver, kidney or central nervous system) were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Mutagenicity

Exemestane was not genotoxic in bacteria (Ames test), in V79 Chinese hamster cells, in rat hepatocytes or in the mouse micronucleus assay. Although exemestane was clastogenic in lymphocytes in vitro, it was not clastogenic in two in vivo studies.

Reproductive toxicology

Exemestane was embryotoxic in rats and rabbits at systemic exposure levels similar to those obtained in humans at 25 mg/day. There was no evidence of teratogenicity.

Carcinogenicity

In a two-year carcinogenicity study in female rats, no treatment-related tumors were observed. In male rats the study was terminated on week 92, because of early death by chronic nephropathy. In a two-year carcinogenicity study in mice, an increase in the incidence of hepatic neoplasms in both genders was observed at the intermediate and high doses (150 and 450 mg/kg/day). This finding is considered to be related to the induction of hepatic microsomal enzymes, an effect observed in mice but not in clinical studies. An increase in the incidence of renal tubular adenomas was also noted in male mice at the high dose (450 mg/kg/day). This change is considered to be species- and gender-specific and occurred at a dose which represents 63-fold greater exposure than occurs at the human therapeutic dose. None of these observed effects is considered to be clinically relevant to the treatment of patients with exemestane.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

Povidone K30

Maize starch (bleached)

Starch, pregelatinized (partially)

Sodium starch glycolate, type A

Cellulose microcrystalline type 101

Talc

Silica, colloidal anhydrous

Magnesium stearate

Polysorbate 80

Film-coating:

Polyvinyl alcohol-partly hydrolyzed

Titanium dioxide (E171)

Macrogol 3350

Talc

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

No special storage conditions

6.5 Nature And Contents Of Container

Al/PVC blister.

Pack sizes:

10, 30, 40, 60, 84, 90 and 100 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 of in accordance with local requirements.

7. Marketing Authorisation Holder

Actavis Group PTC ehf

Rekjavíkurvegur 76-78,

220 Hafnarfjörður

Iceland

8. Marketing Authorisation Number(S)

PL 30306/0272

9. Date Of First Authorisation/Renewal Of The Authorisation

06/10/2010

10. Date Of Revision Of The Text

22/07/11

11 DOSIMETRY

(IF APPLICABLE)

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

(IF APPLICABLE)

Tuesday 25 September 2012

Symax SR

Generic Name: hyoscyamine (hye oh SYE a meen)

Brand Names: Anaspaz, Cystospaz, Ed Spaz, HyoMax, HyoMax DT, HyoMax FT, HyoMax SL, HyoMax SR, Hyospaz, Hyosyne, IB-Stat, Levbid, Levsin, Levsin SL, Levsinex SR, NuLev, Nulev, Symax Duotab, Symax FasTab, Symax SL, Symax SR

What is Symax SR (hyoscyamine)?

Hyoscyamine produces many effects in the body, including relief from muscle spasms.

Hyoscyamine also reduces the fluid secretions of many organs and glands in the body, such as the stomach, pancreas, lungs, saliva glands, sweat glands, and nasal passages.

Hyoscyamine is used to treat many different stomach and intestinal disorders, including peptic ulcer and irritable bowel syndrome. It is also used to control muscle spasms in the bladder, kidneys, or digestive tract, and to reduce stomach acid. Hyoscyamine is sometimes used to reduce tremors and rigid muscles in people with symptoms of Parkinson's disease.

Hyoscyamine is also used as a drying agent to control excessive salivation, runny nose, or excessive sweating.

Hyoscyamine may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Symax SR (hyoscyamine)?

Do not take hyoscyamine if you are allergic to it, or if you have kidney disease, a bladder or intestinal obstruction, severe ulcerative colitis, toxic megacolon, glaucoma, or myasthenia gravis.

Before taking hyoscyamine, tell your doctor if you have heart disease, congestive heart failure, a heart rhythm disorder, high blood pressure, overactive thyroid, or hiatal hernia with gastroesophageal reflux disease.

Avoid taking antacids at the same time you take hyoscyamine. Antacids can make it harder for your body to absorb hyoscyamine. If you use an antacid, take it after you have taken hyoscyamine and eaten a meal.

Hyoscyamine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert. Drinking alcohol can increase drowsiness and dizziness while you are taking hyoscyamine.

Avoid becoming overheated or dehydrated during exercise and in hot weather. Hyoscyamine can decrease sweating and you may be more prone to heat stroke.

What should I discuss with my healthcare provider before taking Symax SR (hyoscyamine)?

Do not take hyoscyamine if you are allergic to it, or if you have:

kidney disease;

an enlarged prostate or problems with urination;

intestinal blockage;

severe ulcerative colitis, or toxic megacolon;

glaucoma; or

myasthenia gravis.

To make sure you can safely take hyoscyamine, tell your doctor if you have any of these other conditions:

heart disease, congestive heart failure;

a heart rhythm disorder;

high blood pressure;

overactive thyroid; or

hiatal hernia with GERD (gastroesophageal reflux disease).

FDA pregnancy category C. It is not known whether hyoscyamine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. Hyoscyamine can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take Symax SR (hyoscyamine)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Your medication may come with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.

Hyoscyamine is usually taken before a meal. Follow your doctor's instructions.

Do not crush, chew, or open an extended-release tablet or capsule. It is specially made to release medicine slowly in the body. Breaking or crushing the pill would cause too much of the drug to be released at one time. Your doctor may want you to break an extended-release tablet and take only half of it. Follow your doctor's instructions.

Measure the oral liquid form of hyoscyamine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

The sublingual tablet form of this medication must be placed under the tongue, where it will dissolve. Do not swallow the sublingual tablet whole or wash it down with water. You may drink water after the pill has completely dissolved in your mouth.

Before using hyoscyamine oral spray for the first time, you must prime the spray pump. To do this, spray 3 test sprays into the air and away from your face. Prime the spray pump at least 1 test spray any time you have not used the oral spray for longer than 2 days. Spray until a fine mist appears.

After using the oral spray, try not to swallow right away. Do not rinse your mouth or spit for 5 to 10 minutes after using the oral spray.

Store this medication at room temperature away from moisture and heat.

Do not use hyoscyamine oral spray for more than 30 sprays, even if there is medicine still left in the bottle.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

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

Overdose symptoms may include headache, dizziness, dry mouth, trouble swallowing, nausea, vomiting, blurred vision, hot dry skin, and feeling restless or nervous.

What should I avoid while taking Symax SR (hyoscyamine)?

Avoid becoming overheated or dehydrated during exercise and in hot weather. Hyoscyamine can decrease sweating and you may be more prone to heat stroke.

Symax SR (hyoscyamine) 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 hyoscyamine and call your doctor at once if you have any of these serious side effects:

diarrhea;

confusion, hallucinations;

unusual thoughts or behavior;

fast, pounding, or uneven heart rate;

rash or flushing (warmth, redness, or tingly feeling); or

eye pain.

Less serious side effects may include:

dizziness, drowsiness, feeling nervous;

blurred vision, headache;

sleep problems (insomnia);

nausea, vomiting, bloating, heartburn, or constipation;

changes in taste;

problems with urination;

decreased sweating;

dry mouth; or

impotence, loss of interest in sex, or trouble having an orgasm.

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 Symax SR (hyoscyamine)?

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

amantadine (Symmetrel);

haloperidol (Haldol);

an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate);

phenothiazines such as chlorpromazine (Thorazine), fluphenazine (Permitil, Prolixin), perphenazine (Trilafon), prochlorperazine (Compazine, Compro), promethazine (Pentazine, Phenergan, Anergan, Antinaus), thioridazine (Mellaril), or trifluoperazine (Stelazine); or

an antidepressant such as amitriptyline (Elavil, Vanatrip), doxepin (Sinequan), desipramine (Norpramin), imipramine (Janimine, Tofranil), nortriptyline (Pamelor), and others.

This list is not complete and other drugs may interact with hyoscyamine. 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 Symax SR resources

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

Symax SR Extended-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Hyoscyamine Monograph (AHFS DI)

Hyoscyamine MedFacts Consumer Leaflet (Wolters Kluwer)

Anaspaz MedFacts Consumer Leaflet (Wolters Kluwer)

HyoMax Prescribing Information (FDA)

Hyosyne Drops MedFacts Consumer Leaflet (Wolters Kluwer)

Hyosyne Prescribing Information (FDA)

IB-Stat Spray MedFacts Consumer Leaflet (Wolters Kluwer)

Levsin Prescribing Information (FDA)

NuLev Orally Disintegrating Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Symax Duotab Controlled-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Symax SR with other medications

Anesthesia
Crohn's Disease
Endoscopy or Radiology Premedication
Irritable Bowel Syndrome
Urinary Incontinence

Where can I get more information?

Your pharmacist can provide more information about hyoscyamine.

See also: Symax SR side effects (in more detail)

Monday 24 September 2012

Carbocaine

Generic Name: mepivacaine (me PIV a kane)

Brand Names: Carbocaine, Carbocaine HCl, Polocaine, Polocaine-MPF

What is Carbocaine (mepivacaine)?

Mepivacaine is an anesthetic (numbing medicine) that blocks the nerve impulses that send pain signals to your brain.

Mepivacaine is used as a local (in only one area) anesthetic for an epidural or spinal block. It is also used as an anesthetic for dental procedures.

Mepivacaine may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Carbocaine (mepivacaine)?

You should not receive mepivacaine if you have ever had an allergic reaction to any type of numbing medicine.

Before receiving this medication, tell your doctor if you have liver disease, kidney disease, high or low blood pressure, asthma or a sulfite allergy, a history of heart disease or stroke, heart block or coronary artery disease, a heart rhythm disorder, or a thyroid disorder.

This medication can cause numbness for an extended period of time. Avoid eating, chewing gum, or drinking hot liquids until the feeling in your mouth has returned completely. Chewing while your mouth is numb could result in a bite injury to your tongue, lips, or inside of your cheek.

What should I discuss with my health care provider before receiving Carbocaine (mepivacaine)?

You should not receive mepivacaine if you have ever had an allergic reaction to any type of numbing medicine.

Before receiving mepivacaine, tell your doctor if you are allergic to any drugs, or if you have:

liver disease;

kidney disease;

low or high blood pressure;

asthma or a sulfite allergy;

a history of heart disease or stroke;

heart block or coronary artery disease;

a heart rhythm disorder; or

a thyroid disorder.

If you have any of these conditions, you may need a dose adjustment or special precautions to safely receive mepivacaine.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Before you receive mepivacaine, tell your doctor if you are pregnant. It is not known whether mepivacaine passes into breast or if it could harm a nursing baby. Before you receive mepivacaine, tell your doctor if you are breast-feeding a baby.

How is mepivacaine given?

Mepivacaine is given as an injection placed into an area of your lower back near your spine. You will receive this injection in a hospital or surgical setting.

When used for a dental procedure, mepivacaine is given as an injection that is usually placed into the gum area inside your mouth. You will receive this injection in a dentist's office or oral surgical setting.

Spinal numbing medications can have long-lasting or permanent effects on certain body processes such as sexual function, bowel or bladder control, and movement or feeling in your legs or feet. Talk with your doctor about your specific risk of nerve damage from mepivacaine. Your breathing, blood pressure, oxygen levels, and other vital signs may be watched closely while you are receiving mepivacaine.

What happens if I miss a dose?

Since mepivacaine is given as needed before a surgery or other medical procedure, you are not likely to be on a dosing schedule.

What happens if I overdose?

Tell your caregivers right away if you think you have received too much of this medicine.

Overdose symptoms may include extreme drowsiness, fainting, seizure (convulsions), shallow breathing, or slow heart rate.

What should I avoid after receiving Carbocaine (mepivacaine)?

Carbocaine (mepivacaine) side effects

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

weak or shallow breathing;

feeling like you might pass out;

sweating, anxiety, confusion;

blurred vision, ringing in your ears;

numbness or tingling around your mouth;

slow heart rate, weak pulse;

metallic taste in your mouth;

tremors, muscle twitching; or

seizure (convulsions).

Less serious side effects may include:

nausea, vomiting;

nervousness;

dizziness; or

drowsiness.

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Carbocaine (mepivacaine)?

Before receiving mepivacaine, tell your doctor if you are using any of the following drugs:

cold medicine, diet pills, stimulants, or medication to treat ADHD;

medicine to treat a psychiatric disorder (Haldol, Inapsine, Thorazine, Prolixin, Serentil, Mellaril, and others);

medication to treat nausea and vomiting, such as Compazine or Motillium;

ergot medicine such as ergotamine (Ergomar, Cafergot), dihydroergotamine (D.H.E. 45, Migranal), ergonovine (Ergotrate), or methylergonovine (Methergine);

an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate); or

antidepressants such as amitriptyline (Elavil, Etrafon), desipramine (Norpramin), imipramine (Janimine, Tofranil), nortriptyline (Pamelor), and others.

This list is not complete and there may be other drugs that can interact with mepivacaine. 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.

More Carbocaine resources

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

Carbocaine MedFacts Consumer Leaflet (Wolters Kluwer)

Carbocaine Prescribing Information (FDA)

Mepivacaine Prescribing Information (FDA)

Compare Carbocaine with other medications

Local Anesthesia

Where can I get more information?

Your doctor or pharmacist can provide more information about mepivacaine.

See also: Carbocaine side effects (in more detail)

Saturday 22 September 2012

Aminophylline Injection BP 500 mg / 2 ml

1. Name Of The Medicinal Product

Aminophylline injection B.P. 500 mg /2 ml.

2. Qualitative And Quantitative Composition

Each 2 ml of solution contains Aminophylline Hydrate B.P. 500 mg equivalent to 479.45mg aminophylline.

3. Pharmaceutical Form

Clear, sterile solution for injection, intended for parenteral administration to human beings.

4. Clinical Particulars

4.1 Therapeutic Indications

Aminophylline is a complex of theophylline and ethylenediamine and is given for its theophylline activity to relax smooth muscle and to relieve bronchial spasm.

Aminophylline injection is indicated for relief of bronchospasm associated with asthma and in chronic obstructive pulmonary disease.

4.2 Posology And Method Of Administration

Aminophylline Injection B.P. 500mg/2ml is for deep intramuscular injection.

Adults:

For adult patients, including the elderly, a single dose of 500mg (2ml) may be administered by deep intramuscular injection.

Children:

Aminophylline Injection (intramuscular) 500mg in 2ml is not suitable for use in children.

For maintenance therapy, Aminophylline Injection (intravenous) 250mg in 10ml can be administered via larger volume infusion solutions, rate-regulated to deliver the required amount of drug each hour.

Therapeutic plasma concentrations of theophylline are considered to be in the range of 5 to 20mcg/ml and levels above 20mcg/ml are more likely to be associated with toxic effects. There is marked interpatient variation in the dosage required to achieve plasma levels of theophylline that are within the desired therapeutic range.

During therapy, patients should be monitored carefully for signs of toxicity and, where possible, the serum theophylline levels should also be monitored.

4.3 Contraindications

Aminophylline should not be administered to patients with a known hypersensitivity to the xanthine group of drugs.

4.4 Special Warnings And Precautions For Use

Elderly patients, or those with cardiac or hepatic disease should be monitored carefully for signs of theophylline toxicity. Children are particularly susceptible to the effects of theophylline and care is required when administrating aminophylline to children. There have been reports of seizures in children with theophylline plasma levels within the accepted therapeutic range. Alternative treatment should be considered in patients with a history of seizure activity and, if Aminophylline Injection is used in such patients, they should be carefully observed for possible signs of central stimulation.

Because the mean half-life of theophylline is shorter in smokers than in nonsmokers, the former group may require larger doses of aminophylline.

To reduce the undesirable stimulating effects of aminophylline on the central nervous and cardiovascular systems, intravenous administration of the drug should be slow and should not exceed a rate of 25 mg/min.

Methylxanthines may increase gastric acidity and care should be taken when they are used in patients with a history of peptic ulceration.

Aminophylline should not be administered concurrently with other xanthine medications.

The label shall contain the following statements:-

Protect from light.

Store below 25°C.

If only part used discard the remaining solution.

Discard the ampoule if the contents are discoloured.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Increased serum levels of theophylline have been reported in patients who were also taking cimetidine, erythromycin, ciprofloxacin, allopurinol, thiabendazole, diltiazem or oral contraceptives. Factors such as viral infection or cardiac failure can also reduce theophylline clearance. There is an increased likelihood of toxicity occurring if ephedrine or other sympathomimetic agents are given concomitantly with aminophylline.

The concomitant use of theophylline and fluvoxamine should usually be avoided. Where this is not possible, patients should have their theophylline dose halved and plasma theophylline should be monitored closely. Factors such as cardiac failure or viral infection, including infection with influenza virus, can also reduce theophylline clearance.

Smoking can increase clearance of theophylline, as can carbamazepine, phenytoin, rifampicin and sulphinpyrazone.

Xanthines can potentiate hypokalaemia resulting from beta2 agonist therapy, steroids, diuretics and hypoxia. Particular caution is advised in severe asthma. It is recommended that serum potassium levels are monitored in such situations.

4.6 Pregnancy And Lactation

As with other drugs, aminophylline should only be used during pregnancy if considered essential by the physician. Theophylline crosses the placenta and is secreted into breast milk.

4.7 Effects On Ability To Drive And Use Machines

Nil.

4.8 Undesirable Effects

Aminophylline may cause gastro-intestinal irritation, with nausea, vomiting and abdominal pain. Symptoms of central nervous system stimulation may occur, including insomnia, restlessness and anxiety. Theophylline can precipitate cardiac arrhythmias and hypotension may follow intravenous injection, particularly if the injection is too rapid. Allergic reactions to aminophylline may occur.

4.9 Overdose

Signs of overdosage may include gastrointestinal disturbances such as nausea and vomiting, manifestations of central nervous system stimulation including headache, restlessness and muscle twitching, and cardiovascular reactions such as palpitation and hypotension.

There is no specific antidote and treatment is supportive and symptomatic.

Aminophylline therapy should be discontinued.

Metabolic disturbances, especially hypokalaemia, should be corrected immediately. Intravenous fluids, oxygen and other supportive measures should be administered to correct hypotension, dehydration and acid-base imbalance.

Sympathomimetic agents should be avoided. Diazepam may be administered intravenously to control convulsions. A patent airway should be maintained and artificial respiration may be required for respiratory depression.

Theophylline is dialyzable; charcoal haemoperfusion and haemodialysis should be considered in cases of severe toxicity.

Serial plasma-theophylline concentrations should be measured until a decreasing trend to levels below 20mcg/ml has been demonstrated.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Aminophylline is a complex of theophylline and ethylenediamine and is given for its theophylline activity to relax smooth muscle and to relieve bronchial spasm.

Theophylline is a smooth muscle relaxant and it relaxes the smooth muscle of the bronchial airways. Other actions of theophylline include cardiac stimulation, CNS stimulation, decreased peripheral vascular resistance and diuresis.

5.2 Pharmacokinetic Properties

Theophylline is approximately 60% bound to plasma proteins but binding is decreased to about 40% in neonates and in adults with hepatic disease. The drug is widely distributed and it crosses the placenta and passes into breast milk.

Theophylline is metabolised in the liver and the metabolites are excreted in the urine. In adults, about 10% of a dose of theophylline is excreted unchanged in the urine. There is considerable inter-individual variation in the rate of hepatic metabolism of theophylline, resulting in large variations in clearance, serum concentrations and half-lives. Cigarette smoking increases theophylline clearance and shortens its serum half-life.

5.3 Preclinical Safety Data

No further relevant information other than that which is included in other sections of the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Ethylenediamine Ph. Eur.

Water for Injections B.P.

6.2 Incompatibilities

Incompatibility has been reported with chlorpromazine, clindamycin, corticotrophin, dimenhydrinate, doxorubicin, erythromycin gluceptate, hydralazine hydrochloride, hydroxyzine hydrochloride, opioid analgesics, oxytetracycline hydrochloride, phenytoin sodium, procaine hydrochloride, prochlorperazine salts, promazine hydrochloride, promethazine hydrochloride, sulphafurazole diethanolamine and vancomycin hydrochloride.

6.3 Shelf Life

Unopened : 3 years (36 months)

After reconstitution: not applicable.

After first opening : not applicable*

*If only part of an ampoule is used, discard the remaining solution.

6.4 Special Precautions For Storage

Protect from light.

Store below 25°C.

6.5 Nature And Contents Of Container

2ml, clear glass ampoules, glass type 1 Ph. Eur. borosilicate glass presented in cardboard cartons to contain 10 x 2ml ampoules.

6.6 Special Precautions For Disposal And Other Handling

For deep intramuscular injection.

Use as directed by the physician.

Keep out of reach of children.

If only part used, discard the remaining solution.

Discard the ampoule if the contents are discoloured.

Administrative Data

7. Marketing Authorisation Holder

Antigen International Ltd.,

Roscrea,

Co. Tipperary,

Ireland.

8. Marketing Authorisation Number(S)

PL 2848/5939R.

9. Date Of First Authorisation/Renewal Of The Authorisation

13/03/2009

10. Date Of Revision Of The Text

13/03/2009

Wednesday 19 September 2012

Levetiracetam 250 mg film-coated tablets

1. Name Of The Medicinal Product

Levetiracetam 250 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 250 mg levetiracetam.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet

Blue, oblong, biconvex coated tablets, scored on both sides and debossed with L9TT/250 on one side

The scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4. Clinical Particulars

4.1 Therapeutic Indications

Levetiracetam is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation in patients from 16 years of age with newly diagnosed epilepsy.

Levetiracetam is indicated as adjunctive therapy

• in the treatment of partial onset seizures with or without secondary generalisation in adults, children and infants from 1 month of age with epilepsy.

• in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy.

• in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalised Epilepsy.

4.2 Posology And Method Of Administration

Posology

Monotherapy for adults and adolescents from 16 years of age

The recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can be further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum dose is 1500 mg twice daily.

Add-on therapy for adults (

The initial therapeutic dose is 500 mg twice daily. This dose can be started on the first day of treatment.

Depending upon the clinical response and tolerability, the daily dose can be increased up to 1,500 mg twice daily. Dose changes can be made in 500 mg twice daily increases or decreases every two to four weeks.

Special population

Elderly (65 years and older)

Adjustment of the dose is recommended in elderly patients with compromised renal function (see "Patients with renal impairment" below).

Patients with renal impairment

The daily dose must be individualised according to renal function.

For adult patients, refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in ml/min is needed. The CLcr in ml/min may be estimated from serum creatinine (mg/dl) determination, for adults and adolescents weighting 50 kg or more, the following formula:

Then CLcr is adjusted for body surface area (BSA) as follows:

Dosing adjustment for adult patients with impaired renal function

Group	Creatinine clearance (ml/min/1.73m²)	Dosage and frequency
Normal	> 80	500 to 1,500 mg twice daily
Mild	50-79	500 to 1,000 mg twice daily
Moderate	30-49	250 to 750 mg twice daily
Severe	< 30	250 to 500 mg twice daily
End-stage renal disease patients undergoing dialysis (1)	-	500 to 1,000 mg once daily (2)

(1) A 750 mg loading dose is recommended on the first day of treatment with levetiracetam.

(2) Following dialysis, a 250 to 500 mg supplemental dose is recommended.

For children with renal impairment, levetiracetam dose needs to be adjusted based on the renal function as levetiracetam clearance is related to renal function. This recommendation is based on a study in adult renally impaired patients.

The CLcr in ml/min/1.73 m² may be estimated from serum creatinine (mg/dl) determination using, for young adolescents, children and infants, using the following formula (Schwartz formula):

ks= 0.45 in Term infants to 1 year old; ks= 0.55 in Children to less than 13 years;

ks= 0.7 in adolescent male

Dosing adjustment for infants and children patients with impaired renal function

Group	Creatinine clearance (ml/min/1.73m²)	Dosage frequency
Infants 1 to less than 6 months	Infants 6 to 23 months, children and adolescents weighing less than 50 kg
Normal	> 80	7 to 21 mg/kg (0.07 to 0.21 ml/kg) twice daily	10 to 30 mg/kg (0.10 to 0.30 ml/kg) twice daily
Mild	50-79	7 to 14 mg/kg (0.07 to 0.14 ml/kg) twice daily	10 to 20 mg/kg (0.10 to 0.20 ml/kg) twice daily
Moderate	30-49	3.5 to 10.5 mg/kg (0.035 to 0.105 ml/kg) twice daily	5 to 15 mg/kg (0.05 to 0.15 ml/kg) twice daily
Severe	< 30	3.5 to 7 mg/kg (0.035 to 0.07 ml/kg) twice daily	5 to 10 mg/kg (0.05 to 0.10 ml/kg) twice daily
End-stage renal disease patients undergoing dialysis		7 to 14 mg/kg (0.07 to 0.14 ml/kg) once daily (1) (3)	10 to 20 mg/kg (0.10 to 0.20 ml/kg) once daily (2) (4)

(1) A 10.5 mg/kg (0.105 ml/kg) loading dose is recommended on the first day of treatment with levetiracetam.

(2) A 15 mg/kg (0.15 ml/kg) loading dose is recommended on the first day of treatment with levetiracetam.

(3) Following dialysis, a 3.5 to 7 mg/kg (0.035 to 0.07 ml/kg) supplemental dose is recommended.

(4) Following dialysis, a 5 to 10 mg/kg (0.05 to 0.10 ml/kg) supplemental dose is recommended.

Hepatic impairment

No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate the renal insufficiency. Therefore a 50 % reduction of the daily maintenance dose is recommended when the creatinine clearance is < 60 ml/min/1.73 m

Paediatric population

The physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to weight and dose.

Monotherapy

The safety and efficacy of levetiracetam in children and adolescents below 16 years as monotherapy treatment have not been established. There are no data available.

Add-on therapy for infants aged from 6 to 23 months, children (2 to 11 years) and adolescents (12 to 17 years) weighing less than 50 kg

The initial therapeutic dose is 10 mg/kg twice daily.

Depending upon the clinical response and tolerability, the dose can be increased up to 30 mg/kg twice daily. Dose changes should not exceed increases or decreases of 10 mg/kg twice daily every two weeks. The lowest effective dose should be used.

Dosage in children 50 kg or greater is the same as in adults.

Dose recommendations for infants from 6 months of age, children and adolescents:

Weight	Starting dose: 10 mg/kg twice daily	Maximum dose: 30 mg/kg twice daily
6 kg ⁽¹⁾	60 mg (0.6 mL) twice daily	180 mg (1.8 mL) twice daily
10 kg ⁽¹⁾	100 mg (1 mL) twice daily	300 mg (3 mL) twice daily
15 kg ⁽¹⁾	150 mg (1.5 mL) twice daily	450 mg (4.5 mL) twice daily
20 kg ⁽¹⁾	200 mg (2 mL) twice daily	600 mg (6 mL) twice daily
25 kg	250 mg twice daily	750 mg twice daily
From 50 kg ⁽²⁾	500 mg twice daily	1500 mg twice daily

(1) Children 20 kg or less should preferably start the treatment with levetiracetam 100 mg/ml oral solution.

(2) Dose in children and adolescents 50 kg or more is the same as in adults.

Add-on therapy for infants from 1 month to less than 6 months

The tablet formulation is not adapted for use in infants under the age of 6 months. The oral solution is the formulation to use in infants.

Method of administration

The film-coated tablets must be taken orally, swallowed with a sufficient quantity of liquid and may be taken with or without food. The daily dose is administered in two equally divided doses.

4.3 Contraindications

Hypersensitivity to levetiracetam or other pyrrolidone derivatives or any of the excipients.

4.4 Special Warnings And Precautions For Use

Discontinuation

In accordance with current clinical practice, if levetiracetam has to be discontinued it is recommended to withdraw it gradually (e.g. in adults: 500 mg decreases twice daily every two to four weeks; in infants older than 6 months, children and adolescents weighting less than 50 kg: dose decrease should not exceed 10 mg/kg twice daily every two weeks; in infants (less than 6 months): dose decrease should not exceed 7 mg/kg twice daily every two weeks).

Renal insufficiency

The administration of levetiracetam to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection (see section 4.2).

Suicide

Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of anti-epileptic drugs has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known.

Therefore patients should be monitored for signs of depression and/or suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of depression and/or suicidal ideation or behaviour emerge.

Paediatric population

The tablet formulation is not adapted for use in infants under the age of 6 months.

Available data in children did not suggest impact on growth and puberty. However, long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.

An increase in seizure frequency of more than 25 % was reported in 14 % of levetiracetam treated adult and paediatric patients (4 to 16 years of age) with partial onset seizures, whereas it was reported in 26 % and 21 % of placebo treated adult and paediatric patients, respectively. When levetiracetam was used to treat primary generalised tonic-clonic seizures in adults and adolescents with idiopathic generalised epilepsy, there was no effect on the frequency of absences.

The safety and efficacy of levetiracetam has not been thoroughly assessed in infants aged less than 1 year. Only 35 infants aged less than 1 year have been exposed in clinical studies of which only 13 were aged < 6 months.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Antiepileptic medicinal products

Pre-marketing data from clinical studies conducted in adults indicate that levetiracetam did not influence the serum concentrations of existing antiepileptic medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these antiepileptic medicinal products did not influence the pharmacokinetics of levetiracetam.

As in adults, there is no evidence of clinically significant medicinal product interactions in paediatric patients receiving up to 60 mg/kg/day levetiracetam.

A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4 to 17 years) confirmed that adjunctive therapy with orally administered levetiracetam did not influence the steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data suggested a 20% higher levetiracetam clearance in children taking enzyme-inducing antiepileptic medicinal products. Dosage adjustment is not required.

Probenecid

Probenecid (500 mg four times daily), a renal tubular secretion blocking agent, has been shown to inhibit the renal clearance of the primary metabolite but not of levetiracetam. Nevertheless, the concentration of this metabolite remains low. It is expected that other medicinal products excreted by active tubular secretion could also reduce the renal clearance of the metabolite. The effect of levetiracetam on probenecid was not studied and the effect of levetiracetam on other actively secreted medicinal products, e.g. NSAIDs, sulfonamides and methotrexate, is unknown.

Oral contraceptives and other pharmacokinetics interactions

Levetiracetam 1,000 mg daily did not influence the pharmacokinetics of oral contraceptives (ethinyl-estradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone) were not modified. levetiracetam 2,000 mg daily did not influence the pharmacokinetics of digoxin and warfarin; prothrombin times were not modified. Co-administration with digoxin, oral contraceptives and warfarin did not influence the pharmacokinetics of levetiracetam.

Antacids

No data on the influence of antacids on the absorption of levetiracetam are available.

Food and alcohol

The extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced.

No data on the interaction of levetiracetam with alcohol are available.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of levetiracetam in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for human is unknown. Levetiracetam is not recommended during pregnancy and in women of childbearing potential not using contraception unless clearly necessary.

As with other antiepileptic drugs, physiological changes during pregnancy may affect levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester (up to 60% of baseline concentration before pregnancy). Appropriate clinical management of pregnant women treated with levetiracetam should be ensured. Discontinuation of antiepileptic treatments may result in exacerbation of the disease which could be harmful to the mother and the foetus.

Breastfeeding

Levetiracetam is excreted in human breast milk. Therefore, breast-feeding is not recommended. However, if levetiracetam treatment is needed during breastfeeding, the benefit/risk of the treatment should be weighed considering the importance of breastfeeding.

Fertility

No impact on fertility was detected in animal studies (see section 5.3). No clinical data are available, potential risk for human is unknown.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Due to possible different individual sensitivity, some patients might experience somnolence or other central nervous system related symptoms, especially at the beginning of treatment or following a dose increase. Therefore, caution is recommended in those patients when performing skilled tasks, e.g. driving vehicles or operating machinery. Patients are advised not to drive or use machines until it is established that their ability to perform such activities is not affected.

4.8 Undesirable Effects

Summary of the safety profile

Pooled safety data from clinical studies conducted with levetiracetam oral formulations in adult patients with partial onset seizures showed that 46.4 % of the patients in the levetiracetam group and 42.2 % of the patients in the placebo group experienced undesirable effects. Serious undesirable effects were experienced in 2.4% of the patients in the levetiracetam and 2.0% of the patients in the placebo groups. The most commonly reported undesirable effects were somnolence, asthenia and dizziness. In the pooled safety analysis, there was no clear dose-response relationship but incidence and severity of the central nervous system related undesirable effects decreased over time.

In monotherapy 49.8 % of the subjects experienced at least one drug related undesirable effect. The most frequently reported undesirable effects were fatigue and somnolence.

A study conducted in adults and adolescents with myoclonic seizures (12 to 65 years) showed that 33.3% of the patients in the levetiracetam group and 30.0% of the patients in the placebo group experienced undesirable effects that were judged to be related to treatment. The most commonly reported undesirable effects were headache and somnolence. The incidence of undesirable effects in patients with myoclonic seizures was lower than that in adult patients with partial onset seizures (33.3% versus 46.4%).

A study conducted in adults and children (4 to 65 years) with idiopathic generalised epilepsy with primary generalised tonic-clonic seizures showed that 39.2 % of the patients in the Levetiracetam group and 29.8 % of the patients in the placebo group experienced undesirable effects that were judged to be related to treatment. The most commonly reported undesirable effect was fatigue.

When Levetiracetam was used to treat primary generalised tonic-clonic seizures in adults and adolescents with idiopathic generalised epilepsy, there was no effect on the frequency of absences.

Tabulated list of adverse reactions

Adverse reactions reported in clinical studies (adults, adolescents, children and infant > 1 month) or from post-marketing experience are listed in the following table per System Organ Class and per frequency. For clinical trials, the frequency is defined as follows: very common (

- Infections and infestations

Common: infection, nasopharyngitis

- Blood and lymphatic system disorders

Common: thrombocytopenia

Post-marketing experience: leukopenia, neutropenia, pancytopenia (with bone marrow suppression identified in some of the cases).

- Metabolism and nutrition disorders

Common: anorexia, weight increase.

The risk of anorexia is higher when topiramate is coadministered with levetiracetam.

Post-marketing experience: weight loss

- Psychiatric disorders

Common: agitation, depression, emotional lability/mood swings, hostility/aggression, insomnia, nervousness/irritability, personality disorders, thinking abnormal

Post-marketing experience: abnormal behaviour, anger, anxiety, confusion, hallucination, psychotic disorder, suicide, suicide attempt and suicidal ideation

- Nervous system disorders

Very common: somnolence

Common: amnesia, ataxia, convulsion, dizziness, headache, hyperkinesia, tremor, balance disorder, disturbance in attention, memory impairment.

Post-marketing experience: paraesthesia

- Eye disorders

Common: diplopia, vision blurred

- Ear and labyrinth disorders

Common: vertigo

- Respiratory, thoracic and mediastinal disorders

Common: cough increased

- Gastrointestinal disorders

Common: abdominal pain, diarrhoea, dyspepsia, nausea, vomiting

Post-marketing experience: pancreatitis

- Hepatobiliary disorders:

Post-marketing experience: hepatic failure, hepatitis, liver function test abnormal

- Skin and subcutaneous tissue disorders

Common: rash, eczema, pruritus

Post-marketing experience: alopecia: in several cases, recovery was observed when levetiracetam was discontinued.

- Musculoskeletal and connective tissue disorders

Common: myalgia

- General disorders and administration site conditions

Very common: asthenia/fatigue.

- Injury, poisoning and procedural complications

Common: accidental injury

Description of selected adverse reactions

The risk of anorexia is higher when topiramate is coadministered with levetiracetam.

In several cases of alopecia, recovery was observed when levetiracetam was discontinued.

Paediatric population

A study conducted in paediatric patients (4 to 16 years) with partial onset seizures showed that 55.4 % of the patients in the levetiracetam group and 40.2 % of the patients in the placebo group experienced undesirable effects. Serious undesirable effects were experienced in 0.0 % of the patients in the levetiracetam group and 1.0 % of the patients in the placebo group. The most commonly reported undesirable effects were somnolence, hostility, nervousness, emotional lability, agitation, anorexia, asthenia and headache in the paediatric population. Safety results in paediatric patients were consistent with the safety profile of levetiracetam in adults except for behavioural and psychiatric adverse events which were more common in children than in adults (38.6% versus 18.6%). However, the relative risk was similar in children as compared to adults.

A study conducted in paediatric patients (1 month to less than 4 years) with partial onset seizures showed that 21.7 % of the patients in the levetiracetam group and 7.1 % of the patients in the placebo group experienced undesirable effects. No Serious undesirable effects were experienced in patients in the levetiracetam or Placebo group. During the long-term follow-up study N01148, the most frequent drug-related treatment-emergent adverse events in the 1m - <4y group were irritability (7.9%), convulsion (7.2%), somnolence (6.6%), psychomotor hyperactivity (3.3%), sleep disorder (3.3%), and aggression (3.3%). Safety results in paediatric patients were consistent with the safety profile of levetiracetam in older children aged 4 to 16 years.

A double-blind, placebo-controlled paediatric safety study with a non-inferiority design has assessed the cognitive and neuropsychological effects of levetiracetam in children 4 to 16 years of age with partial onset seizures. It was concluded that levetiracetam was not different (non inferior) from placebo with regard to the change from baseline of the Leiter-R Attention and Memory, Memory Screen Composite score in the per-protocol population. Results related to behavioral and emotional functioning indicated a worsening in levetiracetam treated patients on aggressive behaviour as measured in a standardized and systematic way using a validated instrument (CBCL - Achenbach Child Behaviour Checklist). However subjects, who took levetiracetam in the long-term open label follow-up study, did not experience a worsening, on average, in their behavioural and emotional functioning; in particular measures of aggressive behaviour were not worse than baseline.

4.9 Overdose

Symptoms

Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with levetiracetam overdoses.

Management of overdose

After an acute overdose, the stomach may be emptied by gastric lavage or by induction of emesis. There is no specific antidote for levetiracetam. Treatment of an overdose will be symptomatic and may include haemodialysis. The dialyser extraction efficiency is 60 % for levetiracetam and 74 % for the primary metabolite.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antiepileptics, other antiepileptics, ATC code: N03AX14

The active substance, levetiracetam, is a pyrrolidone derivative (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine acetamide), chemically unrelated to existing antiepileptic active substances.

Mechanism of action

The mechanism of action of levetiracetam still remains to be fully elucidated but appears to be different from the mechanisms of current antiepileptic medicinal products. In vitro and in vivo experiments suggest that levetiracetam does not alter basic cell characteristics and normal neurotransmission.

In vitro studies show that levetiracetam affects intraneuronal Ca2+ levels by partial inhibition of N-type Ca2+ currents and by reducing the release of Ca2+ from intraneuronal stores. In addition it partially reverses the reductions in GABA- and glycine-gated currents induced by zinc and β-carbolines. Furthermore, levetiracetam has been shown in in vitro studies to bind to a specific site in rodent brain tissue. This binding site is the synaptic vesicle protein 2A, believed to be involved in vesicle fusion and neurotransmitter exocytosis. Levetiracetam and related analogs show a rank order of affinity for binding to the synaptic vesicle protein 2A which correlates with the potency of their anti-seizure protection in the mouse audiogenic model of epilepsy. This finding suggests that the interaction between levetiracetam and the synaptic vesicle protein 2A seems to contribute to the antiepileptic mechanism of action of the medicinal product.

Pharmacodynamic effects

Levetiracetam induces seizure protection in a broad range of animal models of partial and primary generalised seizures without having a pro-convulsant effect. The primary metabolite is inactive.

In man, an activity in both partial and generalised epilepsy conditions (epileptiform discharge/photoparoxysmal response) has confirmed the broad spectrum pharmacological profile of levetiracetam.

Clinical experience

Adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents, children and infants from 1 month of age with epilepsy:

In adults, levetiracetam efficacy has been demonstrated in 3 double-blind, placebo-controlled studies at 1000 mg, 2000 mg, or 3000 mg/day, given in 2 divided doses, with a treatment duration of up to 18 weeks. In a pooled analysis, the percentage of patients who achieved 50% or greater reduction from baseline in the partial onset seizure frequency per week at stable dose (12/14 weeks) was of 27.7%, 31.6% and 41.3% for patients on 1000, 2000 or 3000 mg levetiracetam respectively and of 12.6% for patients on placebo.

Paediatric population

In paediatric patients (4 to 16 years of age), levetiracetam efficacy was established in a double-blind, placebo-controlled study, which included 198 patients and had a treatment duration of 14 weeks. In this study, the patients received levetiracetam as a fixed dose of 60 mg/kg/day (with twice a day dosing).

44.6% of the levetiracetam treated patients and 19.6% of the patients on placebo had a 50% or greater reduction from baseline in the partial onset seizure frequency per week. With continued long-term treatment, 11.4% of the patients were seizure-free for at least 6 months and 7.2% were seizure-free for at least 1 year.

In paediatric patients (1 month to less than 4 years of age), levetiracetam efficacy was established in a double-blind, placebo-controlled study, which included 116 patients and had a treatment duration of 5 days. In this study, patients were prescribed 20 mg/kg, 25 mg/kg, 40 mg/kg or 50 mg/kg daily dose of oral solution based on their age titration schedule. A dose of 20 mg/kg/day titrating to 40 mg/kg/day for infants one month to less than six month and a dose of 25 mg/kg/day titrating to 50 mg/kg/day for infants and children 6 month to less than 4 years old, was use in this study. The total daily dose was administered b.i.d.

The primary measure of effectiveness was the responder rate (percent of patients with

Monotherapy in the treatment of partial onset seizures with or without secondary generalisation in patients from 16 years of age with newly diagnosed epilepsy.

Efficacy of levetiracetam as monotherapy was established in a double-blind, parallel group, non-inferiority comparison to carbamazepine controlled release (CR) in 576 patients 16 years of age or older with newly or recently diagnosed epilepsy. The patients had to present with unprovoked partial seizures or with generalized tonic-clonic seizures only. The patients were randomized to carbamazepine CR 400 - 1200 mg/day or levetiracetam 1000 - 3000 mg/day, the duration of the treatment was up to 121 weeks depending on the response.

Six-month seizure freedom was achieved in 73.0% of levetiracetam-treated patients and 72.8% of carbamazepine-CR treated patients; the adjusted absolute difference between treatments was 0.2% (95% CI: -7.8 8.2). More than half of the subjects remained seizure free for 12 months (56.6% and 58.5% of subjects on levetiracetam and on carbamazepine CR respectively).

In a study reflecting clinical practice, the concomitant antiepileptic medication could be withdrawn in a limited number of patients who responded to levetiracetam adjunctive therapy (36 adult patients out of 69).

Adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy.

Levetiracetam efficacy was established in a double-blind, placebo-controlled study of 16 weeks duration, in patients 12 years of age and older suffering from idiopathic generalized epilepsy with myoclonic seizures in different syndromes. The majority of patients presented with juvenile myoclonic epilepsy.

In this study, levetiracetam, dose was 3000 mg/day given in 2 divided doses.

58.3% of the levetiracetam treated patients and 23.3% of the patients on placebo had at least a 50% reduction in myoclonic seizure days per week. With continued long-term treatment, 28.6% of the patients were free of myoclonic seizures for at least 6 months and 21.0% were free of myoclonic seizures for at least 1 year.

Adjunctive therapy in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalised epilepsy.

Levetiracetam efficacy was established in a 24-week double-blind, placebo-controlled study which included adults, adolescents and a limited number of children suffering from idiopathic generalized epilepsy with primary generalized tonic-clonic (PGTC) seizures in different syndromes (juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy, or epilepsy with Grand Mal seizures on awakening). In this study, levetiracetam dose was 3000 mg/day for adults and adolescents or 60 mg/kg/day for children, given in 2 divided doses.

72.2% of the levetiracetam treated patients and 45.2% of the patients on placebo had a 50% or greater decrease in the frequency of PGTC seizures per week. With continued long-term treatment, 47.4% of the patients were free of tonic-clonic seizures for at least 6 months and 31.5% were free of tonic-clonic seizures for at least 1 year.

5.2 Pharmacokinetic Properties

Levetiracetam is a highly soluble and permeable compound. The pharmacokinetic profile is linear with low intra- and inter-subject variability. There is no modification of the clearance after repeated administration. There is no evidence for any relevant gender, race or circadian variability. The pharmacokinetic profile is comparable in healthy volunteers and in patients with epilepsy.

Due to its complete and linear absorption, plasma levels can be predicted from the oral dose of levetiracetam expressed as mg/kg bodyweight. Therefore there is no need for plasma level monitoring of levetiracetam.

A significant correlation between saliva and plasma concentrations has been shown in adults and children (ratio of saliva/plasma concentrations ranged from 1 to 1.7 for oral tablet formulation and after 4 hours post-dose for oral solution formulation).

Adults and adolescents

Absorption

Levetiracetam is rapidly absorbed after oral administration. Oral absolute bioavailability is close to 100 %.

Peak plasma concentrations (_Cmax) are achieved at 1.3 hours after dosing. Steady-state is achieved after two days of a twice daily administration schedule.

Peak concentrations (_Cmax) are typically 31 and 43 µg/ml following a single 1,000 mg dose and repeated 1,000 mg twice daily dose, respectively.

The extent of absorption is dose-independent and is not altered by food.

Distribution

No tissue distribution data are available in humans.

Neither levetiracetam nor its primary metabolite are significantly bound to plasma proteins (< 10 %). The volume of distribution of levetiracetam is approximately 0.5 to 0.7 l/kg, a value close to the total body water volume.

Biotransformation

Levetiracetam is not extensively metabolised in humans. The major metabolic pathway (24 % of the dose) is an enzymatic hydrolysis of the acetamide group. Production of the primary metabolite, ucb L057, is not supported by liver cytochrome P₄₅₀ isoforms. Hydrolysis of the acetamide group was measurable in a large number of tissues including blood cells. The metabolite ucb L057 is pharmacologically inactive.

Two minor metabolites were also identified. One was obtained by hydroxylation of the pyrrolidone ring (1.6 % of the dose) and the other one by opening of the pyrrolidone ring (0.9 % of the dose). Other unidentified components accounted only for 0.6 % of the dose.

No enantiomeric interconversion was evidenced in vivo for either levetiracetam or its primary metabolite.

In vitro, levetiracetam and its primary metabolite have been shown not to inhibit the major human liver cytochrome P₄₅₀ isoforms (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyl transferase (UGT1A1 and UGT1A6) and epoxide hydroxylase activities. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid.

In human hepatocytes in culture, levetiracetam had little or no effect on CYP1A2, SULT1E1 or UGT1A1. Levetiracetam caused mild induction of CYP2B6 and CYP3A4. The in vitro data and in vivo interaction data on oral contraceptives, digoxin and warfarin indicate that no significant enzyme induction is expected in vivo. Therefore, the interaction of levetiracetam with other substances, or vice versa, is unlikely.

Elimination

The plasma half-life in adults was 7±1 hours and did not vary either with dose, route of administration or repeated administration. The mean total body clearance was 0.96 ml/min/kg.

The major route of excretion was via urine, accounting for a mean 95 % of the dose (approximately 93 % of the dose was excreted within 48 hours). Excretion via faeces accounted for only 0.3 % of the dose.

The cumulative urinary excretion of levetiracetam and its primary metabolite accounted for 66 % and 24 % of the dose, respectively during the first 48 hours.

The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml/min/kg respectively indicating that levetiracetam is excreted by glomerular filtration with subsequent tubular reabsorption and that the primary metabolite is also excreted by active tubular secretion in addition to glomerular filtration.

Levetiracetam elimination is correlated to creatinine clearance.

Elderly

In the elderly, the half-life is increased by about 40 % (10 to 11 hours). This is related to the decrease in renal function in this population (see section 4.2).

Renal impairment

The apparent body clearance of both levetiracetam and of its primary metabolite is correlated to the creatinine clearance. It is therefore recommended to adjust the maintenance daily dose of Levetiracetam, based on creatinine clearance in patients with moderate and severe renal impairment (see section 4.2).

In anuric end-stage renal disease adult subjects the half-life was approximately 25 and 3.1 hours during interdialytic and intradialytic periods, respectively.

The fractional removal of levetiracetam was 51 % during a typical 4-hour dialysis session.

Hepatic impairment

In subjects with mild and moderate hepatic impairment, there was no relevant modification of the clearance of levetiracetam. In most subjects with severe hepatic impairment, the clearance of levetiracetam was reduced by more than 50 % due to a concomitant renal impairment (see section 4.2).

Peadiatric population

Children (4 to 12 years)

Following single oral dose administration (20 mg/kg) to epileptic children (6 to 12 years), the half-life of levetiracetam was 6.0 hours. The apparent body weight adjusted clearance was approximately 30 % higher than in epileptic adults.

Following repeated oral dose administration (20 to 60 mg/kg/day) to epileptic children (4 to 12 years), levetiracetam was rapidly absorbed. Peak plasma concentration was observed 0.5 to 1.0 hour after dosing. Linear and dose proportional increases were observed for peak plasma concentrations and area under the curve. The elimination half-life was approximately 5 hours. The apparent body clearance was 1.1 ml/min/kg.

Infants and children (1 month to 4 years)

Following single dose administration (20 mg/kg) of a 100 mg/ml oral solution to epileptic children (1 month to 4 years), levetiracetam was rapidly absorbed and peak plasma concentrations were observed approximately 1 hour after dosing. The pharmacokinetic results indicated that half-life was shorter (5.3 h) than for adults (7.2 h) and apparent clearance was faster (1.5 ml/min/kg) than for adults (0.96 ml/min/kg).

In the population pharmacokinetic analysis conducted in patients from 1 month to 16 years of age, body weight was significantly correlated to apparent clearance (clearance increased with an increase in body weight) and apparent volume of distribution. Age also had an influence on both parameters. This effect was pronounced for the younger infants, and subsided as age increased, to become negligible around 4 years of age.

In both population pharmacokinetic analyses, there was about a 20% increase of apparent clearance of levetiracetam when it was co-administered with an enzyme-inducing AED.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenicity.

Adverse effects not observed in clinical studies but seen in the rat and to a lesser extent in the mouse at exposure levels similar to human exposure levels and with possible relevance for clinical use were liver changes, indicating an adaptive response such as increased weight and centrilobular hypertrophy, fatty infiltration and increased liver enzymes in plasma.

No adverse effects on male or female fertility or reproduction performance were observed in rats at doses up to 1800 mg/kg/day (x 6 the MRHD on a mg/m2 or exposure basis) in parents and F1 generation.

Two embryo-fetal development (EFD) studies were performed in rats at 400, 1200 and 3600 mg/kg/day. At 3600 mg/kg/day, in only one of the 2 EFD studies, there was a slight decrease in fetal weight associated with a marginal increase in skeletal variations/minor anomalies. There was no effect on embryomortality and no increased incidence of malformations. The NOAEL (No Observed Adverse Effect Level) was 3600 mg/kg/day for pregnant female rats (x 12 the MRHD on a mg/m2 basis) and 1200 mg/kg/day for fetuses.

Four embryo-fetal development studies were performed in rabbits covering doses of 200, 600, 800, 1200 and 1800 mg/kg/day. The dose level of 1800 mg/kg/day induced a marked maternal toxicity and a decrease in fetal weight associated with increased incidence of fetuses with cardiovascular/skeletal anomalies. The NOAEL was <200 mg/kg/day for the dams and 200 mg/kg/day for the fetuses (equal to the MRHD on a mg/m2 basis).

A peri- and post-natal development study was performed in rats with levetiracetam doses of 70, 350 and 1800 mg/kg/day. The NOAEL was