Sevredol tablets 10mg, 20mg and 50mg

1. Name Of The Medicinal Product

Sevredol^®tablets 10 mg , 20 mg, 50 mg.

2. Qualitative And Quantitative Composition

Morphine Sulphate 10 mg, 20 mg, 50 mg

For excipients see 6.1.

3. Pharmaceutical Form

Film-coated tablet.

10 mg

Blue, film-coated, capsule-shaped, biconvex tablet with a score line on one side. "IR" is marked on the left side and "10" on the right.

20 mg

Pink, film-coated, capsule-shaped, biconvex tablet with a score line on one side. "IR" is marked on the left side and "20" on the right.

50 mg

Pale, green film-coated, capsule-shaped, biconvex tablet with a score line on one side. "IR" is marked on the left side and "50" on the right.

4. Clinical Particulars

4.1 Therapeutic Indications

Sevredol tablets are indicated for the relief of severe pain.

4.2 Posology And Method Of Administration

Route of administration

Oral.

Adults and children over 12 years.

The dosage of Sevredol tablets is dependent on the severity of pain and the patient's previous history of analgesic requirements. One tablet to be taken every four hours or as directed by a physician. Increasing severity of pain or tolerance to morphine will require increased dosage of Sevredol tablets using 10 mg, 20 mg or 50 mg alone or in combination to achieve the desired relief.

Patients receiving Sevredol tablets in place of parenteral morphine should be given a sufficiently increased dosage to compensate for any reduction in analgesic effects associated with oral administration. Usually such increased requirement is of the order of 100%. In such patients individual dose adjustments are required.

Elderly:

A reduction in adult dosage may be advisable.

Children 3 -12 years of age:

Only Sevredol 10 mg and 20 mg tablets are suitable for children:-

3 - 5 years 6 -12 years

5 mg, 4-hourly 5 -10 mg, 4-hourly

Sevredol tablets 50 mg are not recommended for children.

4.3 Contraindications

Hypersensitivity to any of the constituents, respiratory depression, head injury, obstructive airways disease, paralytic ileus, acute abdomen, delayed gastric emptying, known morphine sensitivity, acute hepatic disease, concurrent administration of mono-amine oxidase inhibitors or within two weeks of discontinuation of their use. Not recommended during pregnancy.

Not recommended for children below 3 years of age.

4.4 Special Warnings And Precautions For Use

The major risk of opioid excess is respiratory depression.

As with all narcotics a reduction in dosage may be advisable in the elderly, in hypothyroidism, in renal and chronic hepatic disease. Use with caution in patients with impaired respiratory function, convulsive disorders, acute alcoholism, delirium tremens, raised intracranial pressure, hypotension with hypovolaemia, severe cor pulmonale, opioid dependent patients, patients with a history of substance abuse, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, prostatic hypertrophy, adrenocortical insufficiency, Sevredol tablets should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, Sevredol tablets should be discontinued immediately.

Morphine may lower the seizure threshold in patients with a history of epilepsy.

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

Patients about to undergo additional pain relieving procedures (e.g. surgery, plexus blockade) should not receive Sevredol tablets for 4 hours prior to the intervention . If further treatment with Sevredol tablets is indicated then the dosage should be adjusted to new post-operative requirements. Sevredol tablets should be used with caution pre-operatively and within the first 24 hours post-operatively. Sevredol tablets should also be used with caution following abdominal surgery as morphine impairs intestinal motility and should not be used until the physician is assured of normal bowel function.

The patient may develop tolerance to the drug with chronic use and require progressively higher doses to maintain pain control. Prolonged use of this product may lead to physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy. When a patient no longer requires therapy with morphine, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal

Morphine has an abuse profile similar to other strong agonist opioids. Morphine may be sought and abused by people with latent or manifest addiction disorders. The product should be used with particular care in patients with a history of alcohol and drug abuse.

Abuse of oral dosage forms by parenteral administration can be expected to result in serious adverse events, which may be fatal.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Morphine should be used with caution in patients who are concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anaesthetics, phenothiazines, other tranquilisers, muscle relaxants, antihypertensives and alcohol. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with the usual doses of morphine.

Mixed agonist/antagonist opioid analgesics (e.g. buprenorphine, nalbuphine, pentazocine) should not be administered to a patient who has received a course of therapy with a pure opioid agonist analgesic.

Cimetidine inhibits the metabolism of morphine.

Monoamine oxidase inhibitors are known to interact with narcotic analgesics producing CNS excitation or depression with hyper- or hypotensive crisis. Morphine should not be co-administered with monoamine oxidase inhibitors or within two weeks of such therapy.

Plasma concentrations of morphine may be reduced by rifampicin.

Although there are no pharmacokinetic data available for concomitant use of ritonavir with morphine, ritonavir induces the hepatic enzymes responsible for the glucuronidation of morphine, and may possibly decrease plasma concentrations of morphine.

4.6 Pregnancy And Lactation

Sevredol tablets are not recommended during pregnancy and labour due to the risk of neonatal respiratory depression. Administration to nursing mothers is not recommended as morphine is excreted in breast milk. Withdrawal symptoms may be observed in the new born of mothers undergoing chronic treatment.

4.7 Effects On Ability To Drive And Use Machines

Treatment with Sevredol tablets may cause sedation and it is not recommended that patients drive or use machines if they experience drowsiness.

4.8 Undesirable Effects

In normal doses, the commonest side effects of morphine are nausea, vomiting, constipation and drowsiness. With chronic therapy, nausea and vomiting are unusual with Sevredol tablets but should they occur the tablets can be readily combined with an anti-emetic if required. Constipation may be treated with appropriate laxatives.

Common (incidence of

Body System	Common (	Uncommon (< 1%)
Immune system disorders		Allergic reaction Anaphylactic reaction Anaphylactoid reaction
Psychiatric disorders	Confusion Insomnia Thinking disturbances	Agitation Drug dependence Dysphoria Euphoria Hallucinations Mood altered
Nervous system disorders	Headache Involuntary muscle contractions Myoclonus Somnolence	Convulsions Hypertonia Paraesthesia Syncope Vertigo
Eye disorders		Miosis Visual disturbance
Cardiac disorders		Bradycardia Palpitations Tachycardia
Vascular disorders		Facial flushing Hypertension Hypotension
Respiratory, thoracic and mediastinal disorders	Bronchospasm Cough decreased	Pulmonary oedema Respiratory depression
Gastrointestinal disorders	Abdominal pain Anorexia Constipation Dry mouth Dyspepsia Nausea Vomiting	Gastrointestinal disorders Ileus Taste perversion
Hepatobiliary disorders	Exacerbation of pancreatitis	Biliary pain Increased hepatic enzymes
Skin and subcutaneous tissue disorders	Hyperhidrosis Rash	Urticaria
Renal and urinary disorders		Ureteric spasm Urinary retention
Reproductive system and breast disorders		Amenorrhoea Decreased libido Erectile dysfunction
General disorders and administration site conditions	Asthenia Pruritus	Drug tolerance Drug withdrawal syndrome Malaise Peripheral oedema

The effects of morphine have led to its abuse and dependence may develop with regular, inappropriate use. This is not a major concern in the treatment of patients with severe pain.

4.9 Overdose

Signs of morphine toxicity and overdosage are pin-point pupils, skeletal muscle flaccidity, bradycardia, respiratory depression and hypotension. Circulatory failure and deepening coma may occur in more severe cases. Rhabdomyolysis progressing to renal failure has been reported in opioid overdosage.

Treatment of morphine overdosage:

Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation.

The pure opioid antagonists are specific antidotes against the effects of opioid overdose. Other supportive measures should be employed as needed.

In the case of massive overdosage, administer naloxone 0.8 mg intravenously. Repeat at 2-3 minute intervals as necessary, or by an infusion of 2 mg in 500 ml of normal saline or 5% dextrose (0.004 mg/ml).

The infusion should be run at a rate related to the previous bolus doses administered and should be in accordance with the patient's response. However, because the duration of action of naloxone is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established.

For less severe overdosage, administer naloxone 0.2 mg intravenously followed by increments of 0.1 mg every 2 minutes if required.

Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdosage. Naloxone should be administered cautiously to persons who are known, or suspected, to be physically dependent on morphine. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome.

Gastric contents may need to be emptied as this can be useful in removing unabsorbed drug.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: natural opium alkaloid

ATC code: N02A A01

Morphine acts as an agonist at opiate receptors in the CNS particularly mu and to a lesser extent kappa receptors. mu receptors are thought to mediate supraspinal analgesia, respiratory depression and euphoria and kappa receptors, spinal analgesia, miosis and sedation.

Central Nervous System

The principal actions of therapeutic value of morphine are analgesia and sedation (i.e., sleepiness and anxiolysis). Morphine produces respiratory depression by direct action on brain stem respiratory centers.

Morphine depresses the cough reflex by direct effect on the cough center in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia. Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of narcotic overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of morphine overdose.

Gastrointestinal Tract and Other Smooth Muscle

Morphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm resulting in constipation.

Morphine generally increases smooth muscle tone, especially the sphincters of the gastrointestinal and biliary tracts. Morphine may produce spasm of the sphincter of Oddi, thus raising intrabiliary pressure.

Cardiovascular System

Morphine may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Endocrine System

Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol, oestrogen and testosterone in association with inappropriately low or normal ACTH, LH or FSH levels. Clinical symptoms may be manifest from these hormonal changes.

Other Pharmacologic Effects

In vitro and animal studies indicate various effects of natural opioids, such as morphine, on components of the immune system; the clinical significance of these findings is unknown.

5.2 Pharmacokinetic Properties

Morphine is well absorbed from Sevredol tablets, however first pass metabolism does occur. Apart from the liver, metabolism also occurs in the kidney and intestinal mucosa. The major urinary metabolite is morphine-3-glucuronide but morphine-6-glucuronide is also formed. The half life for morphine in the plasma is approximately 2.5 - 3.0 hours.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core

Lactose (anhydrous)

Pregelatinised maize starch

Povidone

Purified water

Magnesium stearate

Talc

Film coat

10 mg tablet:

Opadry (blue) 06B20843 containing Macrogol 400, E464, E133, E171 Purified water

20 mg tablet:

Hypromellose (5 cps) Hypromellose (15 cps) Macrogol 400 Opaspray (pink) M-1-5503 containing E171, E127, E110 Purified water

50 mg tablet:

Opadry OY-21037 Green (containing hypromellose E464, titanium dioxide E171, macrogol 400, quinoline yellow E104, indigo carmine E132, iron oxide yellow E172)

6.2 Incompatibilities

None known.

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

Do not store above 30^oC.

6.5 Nature And Contents Of Container

PVdC coated PVC blister packs and polypropylene containers with polyethylene lids containing 56 and 112 tablets.

Medical sample packs containing up to 24 tablets are also available.

6.6 Special Precautions For Disposal And Other Handling

None

7. Marketing Authorisation Holder

Napp Pharmaceuticals Ltd

Cambridge Science Park

Milton Road

Cambridge CB4 0GW

8. Marketing Authorisation Number(S)

PL 16950/0063-0065

9. Date Of First Authorisation/Renewal Of The Authorisation

1 May 1999/22 March 2003

10. Date Of Revision Of The Text

November 2007

11 LEGAL CATEGORY

CD (Sch 2), POM

® The Napp device and Sevredol are Registered Trade Marks.

© Napp Pharmaceuticals Limited 2007.

Levetiracetam 500 mg film-coated tablets

1. Name Of The Medicinal Product

Levetiracetam 500 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 500 mg levetiracetam.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet

Yellow, oblong, biconvex coated tablets, scored on both sides and debossed with L9TT/500 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.

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.

Tabulated list of adverse reactions

Adverse reactions reported in clinical studies (adults, adolescents, children and infants > 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

Neonatal and juvenile animal studies in rats and

PSE Carbinoxamine DM

Generic Name: carbinoxamine, dextromethorphan, and pseudoephedrine (kar bi NOX a meen/dex troe meh THOR fan/soo doe eh FEH drin)

Brand Names: Andehist DM NR, Carb PSE 12 DM, Carbaxef-DM, Carbodex DM, Carbofed DM Drops, Cordron-12 DM, Cordron-DM NR, Mintex DM, Pediatex 12 DM, Pediatex-DM, PSE Allergy DM, PSE Carb DM Drops, PSE Carbinoxamine DM, Pseudo Carb DM

What is PSE Carbinoxamine DM (carbinoxamine, dextromethorphan, and pseudoephedrine)?

Carbinoxamine is an antihistamine that reduces the natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose.

Dextromethorphan is a cough suppressant. It suppresses an area in the brain that causes coughing.

Pseudoephedrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).

The combination of carbinoxamine, dextromethorphan, and pseudoephedrine is used to treat sneezing, cough, runny or stuffy nose, itchy or watery eyes, hives, skin rash, itching, and other symptoms of allergies and the common cold.

Carbinoxamine, dextromethorphan, and pseudoephedrine may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about PSE Carbinoxamine DM (carbinoxamine, dextromethorphan, and pseudoephedrine)?

Always ask a doctor before giving a cold or allergy medicine to a child, even if the medicine label provides dosing instructions for children. Death can occur from the misuse of cough and cold medicines in very young children. Do not use carbinoxamine, dextromethorphan, and pseudoephedrine if you have used an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if you take carbinoxamine, dextromethorphan, and pseudoephedrine before the MAO inhibitor has cleared from your body. Carbinoxamine, dextromethorphan, and pseudoephedrine can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. Avoid drinking alcohol. It can increase some of the side effects of this medication.

Call your doctor if you have a fever, or if your symptoms get worse or do not improve after taking this medicine for 7 days.

Do not take this product for cough caused by smoking, asthma, or emphysema. Do not take this medicine if your cough produces a lot of mucus, unless your doctor has told you to.

What should I discuss with my healthcare provider before taking PSE Carbinoxamine DM (carbinoxamine, dextromethorphan, and pseudoephedrine)?

Do not use carbinoxamine, dextromethorphan, and pseudoephedrine if you have used an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if you take carbinoxamine, dextromethorphan, and pseudoephedrine before the MAO inhibitor has cleared from your body.

Before taking this medication, tell your doctor if you are allergic to carbinoxamine, dextromethorphan, or pseudoephedrine, or if you have:

• kidney disease;


• liver disease;


• 
  

  diabetes;

  
  


• 
  

  glaucoma;

  
  


• 
  

  heart disease or high blood pressure;

  
  


• 
  

  thyroid disease;

  
  


• 
  

  a stomach ulcer or a stomach obstruction,

  
  


• 
  

  emphysema or chronic bronchitis; or

  
  


• 
  

  an enlarged prostate or urination problems.

  
  

If you have any of these conditions, you may need a dose adjustment or special tests to safely take this medication.

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. Carbinoxamine, dextromethorphan, and pseudoephedrine 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.

Artificially-sweetened liquid forms of cold medicine may contain phenylalanine. This would be important to know if you have phenylketonuria (PKU). Check the ingredients and warnings on the medication label if you are concerned about phenylalanine.

How should I take PSE Carbinoxamine DM (carbinoxamine, dextromethorphan, and pseudoephedrine)?

Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor. Follow the directions on your prescription label. Cold medicine is usually taken only for a short time until your symptoms clear up.

Always ask a doctor before giving a cold or allergy medicine to a child, even if the medicine label provides dosing intructions for children. Death can occur from the misuse of cough and cold medicines in very young children.

Measure the liquid medicine 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 where you can get one.

Call your doctor if you have a fever, or if your symptoms get worse or do not improve after taking this medicine for 7 days.

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

What happens if I miss a dose?

Since cough and cold medicine is usually taken only as needed, you may not be on a dosing schedule. If you are taking the medication regularly, 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 your 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.

Overdose symptoms may include extreme drowsiness, confusion, feeling restless or nervous, blurred vision, dry mouth, nausea, vomiting, restlessness, hallucinations, fainting, and seizure (convulsions).

What should I avoid while taking PSE Carbinoxamine DM (carbinoxamine, dextromethorphan, and pseudoephedrine)?

This medication can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert. Avoid drinking alcohol. It can increase some of the side effects of this medication. Do not use any other over-the-counter cough, cold, allergy, or sleep medication without first asking your doctor or pharmacist. Antihistamines, decongestants, and cough suppressants are contained in many medicines available over the counter. If you take certain products together you may accidentally take too much of one or more types of medicine. Read the label of any other medicine you are using to see if it contains an antihistamine, decongestant, or cough suppressant. Tell your doctor if you regularly use other medicines that make you sleepy (such as narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression, or anxiety). They can add to sleepiness caused by carbinoxamine or dextromethorphan.

Avoid taking diet pills, caffeine pills, or other stimulants (such as ADHD medications) without your doctor's advice. Taking a stimulant together with a decongestant can increase your risk of unpleasant side effects.

PSE Carbinoxamine DM (carbinoxamine, dextromethorphan, and pseudoephedrine) 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 this medication and call your doctor at once if you have any of these serious side effects:

• 
  

  feeling light-headed, fainting;

  
  


• 
  

  urinating less than usual or not at all;

  
  


• 
  

  wheezing, tightness in your chest;

  
  


• 
  

  severe dizziness, anxiety, restless feeling, or nervousness;

  
  


• 
  

  easy bruising or bleeding, unusual weakness, fever, chills, body aches, flu symptoms; or

  
  


• 
  

  increased blood pressure (severe headache, blurred vision, trouble concentrating, chest pain, numbness, seizure).

  
  

Less serious side effects may include:

• 
  

  drowsiness, dizziness;

  
  


• 
  

  lack of coordination;

  
  


• 
  

  upset stomach;

  
  


• 
  

  stuffy nose, chest congestion;

  
  


• 
  

  sleep problems (insomnia);

  
  


• 
  

  feeling restless or excited (especially in children);

  
  


• 
  

  dry mouth or nose; or

  
  


• 
  

  blurred vision.

  
  

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect.

What other drugs will affect PSE Carbinoxamine DM (carbinoxamine, dextromethorphan, and pseudoephedrine)?

Before taking carbinoxamine, dextromethorphan, and pseudoephedrine, tell your doctor if you are using any of the following drugs:

• 
  

  a diuretic (water pill), or blood pressure medicine;

  
  


• 
  

  medication to treat irritable bowel syndrome;

  
  


• 
  

  bladder or urinary medications such as oxybutynin (Ditropan, Oxytrol) or tolterodine (Detrol);

  
  


• 
  

  aspirin or salicylates (such as Disalcid, Doan's Pills, Dolobid, Salflex, Tricosal, and others);

  
  


• 
  

  a beta-blocker such as atenolol (Tenormin), carteolol (Cartrol), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), timolol (Blocadren), and others; or

  
  


• 
  

  antidepressants such as amitriptyline (Elavil), clomipramine (Anafranil), imipramine (Janimine, Tofranil), and others.

  
  

This list is not complete and there may be other drugs that can interact with carbinoxamine, dextromethorphan, and pseudoephedrine. 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 PSE Carbinoxamine DM resources

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

• Andehist DM NR Drops MedFacts Consumer Leaflet (Wolters Kluwer)


• Cordron-12 DM Suspension MedFacts Consumer Leaflet (Wolters Kluwer)


• Cordron-DM Liquid MedFacts Consumer Leaflet (Wolters Kluwer)

Compare PSE Carbinoxamine DM with other medications

• Cough
• Nasal Congestion

Where can I get more information?

• Your pharmacist can provide more information about carbinoxamine, dextromethorphan, and pseudoephedrine.

See also: PSE Carbinoxamine DM side effects (in more detail)

trazodone

TRAZ-oh-done

Oral route(Tablet;Tablet, Extended Release)

Antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults in short-term studies with major depressive disorder (MDD) and other psychiatric disorders. Short term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24, and there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. This risk must be balanced with the clinical need. Monitor patients closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Not approved for use in pediatric patients .

Commonly used brand name(s)

In the U.S.

• Desyrel


• Desyrel Dividose


• Oleptro

Available Dosage Forms:

• Tablet


• Tablet, Extended Release

Therapeutic Class: Antidepressant

Chemical Class: Triazolopyridine

Uses For trazodone

Trazodone belongs to the group of medicines known as antidepressants or "mood elevators". It is used to relieve mental depression, and depression that sometimes occurs with anxiety.

trazodone is available only with your doctor's prescription.

Before Using trazodone

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For trazodone, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to trazodone or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of trazodone in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of trazodone extended-release tablets in the elderly. However, elderly patients are more likely to have hyponatremia (low sodium in the blood), which may require caution in patients receiving trazodone.

No information is available on the relationship of age to the effects of trazodone regular tablets in the elderly.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking trazodone, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using trazodone with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Cisapride


• Dronedarone


• Linezolid


• Metoclopramide


• Pimozide


• Posaconazole


• Saquinavir


• Sparfloxacin

Using trazodone with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alfuzosin


• Amiodarone


• Amitriptyline


• Amoxapine


• Apomorphine


• Arsenic Trioxide


• Asenapine


• Astemizole


• Azithromycin


• Chloroquine


• Ciprofloxacin


• Citalopram


• Clomipramine


• Clozapine


• Crizotinib


• Dasatinib


• Desipramine


• Disopyramide


• Dofetilide


• Dolasetron


• Droperidol


• Duloxetine


• Erythromycin


• Flecainide


• Fluconazole


• Fluoxetine


• Gatifloxacin


• Gemifloxacin


• Ginkgo


• Granisetron


• Halofantrine


• Haloperidol


• Ibutilide


• Iloperidone


• Imipramine


• Lapatinib


• Levofloxacin


• Lopinavir


• Lumefantrine


• Mefloquine


• Methadone


• Methylene Blue


• Moxifloxacin


• Nilotinib


• Norfloxacin


• Nortriptyline


• Octreotide


• Ondansetron


• Paliperidone


• Paroxetine


• Pazopanib


• Perflutren Lipid Microsphere


• Procainamide


• Propafenone


• Protriptyline


• Quetiapine


• Quinidine


• Quinine


• Ranolazine


• Salmeterol


• Sodium Phosphate


• Sodium Phosphate, Dibasic


• Sodium Phosphate, Monobasic


• Solifenacin


• Sorafenib


• Sotalol


• St John's Wort


• Sunitinib


• Telithromycin


• Terfenadine


• Tetrabenazine


• Toremifene


• Trimipramine


• Vandetanib


• Vardenafil


• Vemurafenib


• Venlafaxine


• Voriconazole


• Ziprasidone

Using trazodone with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Atazanavir


• Carbamazepine


• Chlorpromazine


• Clarithromycin


• Digoxin


• Foxglove


• Indinavir


• Itraconazole


• Ketoconazole


• Nefazodone


• Phenytoin


• Ritonavir


• Thioridazine


• Tipranavir


• Trifluoperazine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Other Medical Problems

The presence of other medical problems may affect the use of trazodone. Make sure you tell your doctor if you have any other medical problems, especially:

• Bipolar disorder (mood disorder with alternating episodes of mania and depression), or risk of or


• Bleeding problems or


• Heart attack, recent or history of or


• Heart disease or


• Heart rhythm problems (e.g., QT prolongation) or


• Hyponatremia (low sodium in the blood) or


• Hypotension (low blood pressure) or


• Priapism (painful or prolonged erection of the penis)—Use with caution. May make these conditions worse.

• Kidney disease or


• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Proper Use of trazodone

Take trazodone only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

trazodone should come with a medication guide. Read and follow these instructions carefully. Talk with your doctor if you have any questions.

To lessen stomach upset and to reduce dizziness and lightheadedness, take the regular tablets with or shortly after a meal or light snack, unless your doctor tells you otherwise.

Take the extended-release tablets at the same time each day, preferably at bedtime, without food.

The tablets can be swallowed whole or given as a half tablet by breaking the tablet along the score line. Do not break the tablets unless your doctor tells you to. Do not crush or chew the tablets.

Dosing

The dose of trazodone will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of trazodone. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For depression:
  
  • For oral dosage form (extended-release tablets):
    
    • Adults—At first, 150 milligrams (mg) once a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 375 mg per day.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For oral dosage form (tablets):
    
    • Adults—At first, 150 milligrams (mg) per day, given in divided doses. Your doctor may adjust your dose as needed. However, the dose is usually not more than 400 mg per day.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of trazodone, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using trazodone

It is very important that your doctor check your progress at regular visits, to allow for changes in your dose and to help manage any side effects.

Do not stop taking trazodone without first checking with your doctor. To prevent a possible return of your medical problem, your doctor may want you to gradually reduce the amount of medicine you are using before you stop completely.

trazodone will add to the effects of alcohol and other CNS depressants (medicines that make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for allergies or colds; sedatives, tranquilizers or sleeping medicine; prescription pain medicine or narcotics; medicine for seizures or barbiturates; muscle relaxants; or anesthetics, including some dental anesthetics. Check with your doctor before taking any of the above while you are using trazodone.

Before having any kind of surgery, dental treatment, or emergency treatment, tell the medical doctor or dentist in charge that you are using trazodone. Taking trazodone together with anesthetic medicines (numbing medicines) that are used during surgery, dental treatments, or emergency treatments may cause an increase in CNS depressant effects.

For some teenagers and young adults, trazodone can increase thoughts of suicide. Tell your doctor right away if you start to feel more depressed or have thoughts about hurting yourself or others. Report any unusual thoughts or behaviors that trouble you, especially if they are new or get worse quickly. Make sure the doctor knows if you have trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. Also tell the doctor if you have sudden or strong feelings, such as feeling nervous, angry, restless, violent, or scared. Let the doctor know if you or anyone in your family have bipolar disorder (manic-depressive disorder) or have tried to commit suicide.

Make sure your doctor knows about all the other medicines you are using. trazodone may cause two serious conditions called serotonin syndrome and neuroleptic malignant syndrome (NMS)-like reactions when taken with certain medicines that are also used for depression, mental conditions, or migraines. Check with your doctor first before taking any other medicines. Stop taking trazodone and tell your doctor right away if you have more than one of the following symptoms: agitation; confusion; diarrhea; difficulty with breathing; a fast heartbeat; a high fever; high or low blood pressure; loss of bladder control; muscle twitching; overactive reflexes; poor coordination; restlessness; seizures; severe muscle stiffness; shivering; sweating; talking or acting with excitement; trembling or shaking that you are unable to control; unusually pale skin; or tiredness.

trazodone can cause changes in the heart rhythm, such as a condition called QT prolongation. It may change the way your heart beats, and cause fainting or serious side effects in some patients. Contact your doctor right away if you have any symptoms of heart rhythm problems, such as fast, pounding, or irregular heartbeats.

trazodone may cause some people to become drowsy or less alert than they are normally. Make sure you know how you react to trazodone before you drive, use machines, or do anything else that could be dangerous if you are not alert.

Dizziness, lightheadedness, or fainting may occur, especially when you get up suddenly from a lying or sitting position. Getting up slowly may help. If this problem continues or gets worse, check with your doctor.

Trazodone may cause dryness of the mouth. For temporary relief, use sugarless gum or candy, melt bits of ice in your mouth, or use a saliva substitute. However, if your mouth continues to feel dry for more than 2 weeks, check with your medical doctor or dentist. Continuing dryness of the mouth may increase the chance of dental disease, including tooth decay, gum disease, and fungus infections.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

trazodone Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Blurred vision


• confusion


• dizziness


• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position


• lightheadedness


• sweating


• unusual tiredness or weakness

Less common

• Burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings


• confusion about identity, place, and time


• decreased concentration


• fainting


• general feeling of discomfort or illness


• headache


• lack of coordination


• muscle tremors


• nervousness


• pounding in the ears


• shortness of breath


• slow or fast heartbeat


• swelling

Rare

• Skin rash


• unusual excitement

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

• Drowsiness


• loss of muscle coordination


• nausea and vomiting


• painful, inappropriate erection of the penis, continuing

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Dryness of the mouth (usually mild)


• muscle or bone pain


• sleeplessness


• trouble with remembering


• trouble with sleeping


• unable to sleep


• unpleasant taste

Less common

• Constipation


• continuing ringing or buzzing or other unexplained noise in the ears


• diarrhea


• hearing loss


• muscle aches or pains


• weight loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: trazodone side effects (in more detail)

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