Trazodone 100mg Capsules (Winthrop Pharmaceuticals UK Ltd)

1. Name Of The Medicinal Product

Trazodone Hydrochloride 100mg Capsules

2. Qualitative And Quantitative Composition

Trazodone hydrochloride 100mg per capsule.

For excipients see 6.1

3. Pharmaceutical Form

Capsules.

4. Clinical Particulars

4.1 Therapeutic Indications

Anxiety, depression, mixed anxiety and depression.

4.2 Posology And Method Of Administration

Route of administration: Oral.

DEPRESSION:

Adults:

Initially 150mg/day in divided doses after food or as a single dose on retiring.

This may be increased up to 300mg/day in a single or divided doses. The major portion of a divided dose to be taken on retiring. The dose may be further increased to 600mg/day in divided doses in hospitalised patients.

Elderly:

For very elderly or frail patients, the recommended initial starting dose is reduced to 100mg/day given in divided doses or as a single night-time dose. This may be incrementally increased, under supervision, according to efficacy and tolerance. In general, single doses above 100mg should be avoided in these patients. It is unlikely that 300mg/day will be exceeded.

Children:

There are insufficient data on safety to recommend the use of Trazodone in children below the age of 18 years.

DEPRESSION ACCOMPANIED BY ANXIETY:

As for depression.

ANXIETY:

75mg/day increasing to 300mg/day as necessary.

A decrease in side-effects (increase of the resorption and decrease of the peak plasma concentration) can be reached by taking Trazodone after a meal..

Hepatic Impairment:

Trazodone undergoes extensive hepatic metabolism, see section 5.2, and has also been associated with hepatotoxicity, see sections 4.4 and 4.8. Therefore caution should be exercised when prescribing for patients with hepatic impairment, particularly in cases of severe hepatic impairment. Periodic monitoring of liver function may be considered.

Renal Impairment:

No dosage adjustment is usually necessary, but caution should be exercised when prescribing for patients with severe renal impairment (see also section 4.4 and 5.2).

4.3 Contraindications

Known sensitivity to trazodone and any of the excipients.

Alcohol intoxication and intoxication with hypnotics.

Acute myocardial infarction.

4.4 Special Warnings And Precautions For Use

Use in children and adolescents under 18

Trazodone should not be used in children and adolescents under 18 years old. Suicidal behaviour (suicidal attempt and suicidal planning) and hostility (essentially aggressiveness, opposing behavior and anger) has been observed in a clinical study on children and adolescents treated with antidepressant more frequently than with placebo. Moreover, long-term safety data on children and adolescents regarding growth, maturation and cognitive and behavioral development are not available.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Other psychiatric conditions for which Trazodone is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

To minimise the potential risk of suicide attempts, particularly at therapy initiation, only restricted quantities of Trazodone should be prescribed at each occasion.

It is recommended that careful dosing and regular monitoring is adopted in patients with the following conditions:

• Epilepsy, specifically abrupt increases or decreases of dosage should be avoided

• Patients with hepatic or renal impairment, particulary if severe

• Patients with cardiac disease, such as angina pectoris, conduction disorders or AV blocks of different degree, recent myocardial infarction

• Hyperthyroidism

• Micturition disorders, such as prostate hypertrophy, although problems would not be anticipated as the anticholinergic effect of Trazodone is only minor

• Acute narrow angle glaucoma, raised intra-ocular pressure, although major changes would not be anticipated due to the minor anticholinergic effect of Trazodone

Should jaundice occur in a patient, Trazodone therapy must be withdrawn.

Administration of antidepressants in patients with schizophrenia or other psychotic disorders may result in a possible worsening of psychotic symptoms. Paranoid thoughts may be intensified. During therapy with Trazodone a depressive phase can change from a manic – depressive psychosis into a manic phase. In that case Trazodone must be stopped.

Interactions in terms of serotonine syndrome/malignant neuroleptic syndrome have been described in case of concomitant use of other serotonergically acting substances like other antidepressants (e.g. tricyclic antidepressants, SSRI's, SNRI's and MAO-inhibitors) and neuroleptics. Malignant neuroleptic syndromes with fatal outcome have been reported in cases of coadministration with neuroleptics, for which this syndrome is a known possible adverse drug reaction. See Sections 4.5 and 4.8 for further information.

Since agranulocytosis may clinically reveal itself with influenza-like symptoms, sore throat, and fever, in these cases it is recommended to check haematology.

Hypotension, including orthostatic hypotension and syncope, has been reported to occur in patients receiving Trazodone. Concomitant administration of antihypertensive therapy with Trazodone may require a reduction in the dose of the antihypertensive drug

Elderly patients are often more sensitive to antidepressants, in particular to orthostatic hypotension and other anticholinergic effects.

Following therapy with Trazodone, particularly for a prolonged period, an incremental dosage reduction to withdrawal is recommended, to minimise the occurrence of withdrawal syptoms, characterised by nausea, headache, and malaise.

There is no evidence that Trazodone hydrochloride possesses any addictive properties.

As with other antidepressant drugs, cases of QT interval prolongation have been reported with Trazodone very rarely. Caution is advised when prescribing Trazodone with medicinal products known to prolong QT interval. Trazodone should be used with caution in patients with known cardiovascular disease including those associated with prolongation of the QT interval.

Potent CYP3A4 inhibitors may lead to increases in trazodone serum levels. See section 4.5 for further information.

As with other drugs with alpha-adrenolytic activity, Trazodone has very rarely been associated with priapism. This may be treated with an intracavernosum injection of an alpha-adrenergic agent such as adrenaline or metaraminol. However there are reports of Trazodone -induced priapism which have required surgical intervention or led to permanent sexual dysfunction. Patients developing this suspected adverse reaction should cease Trazodone immediately.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

General: The sedative effects of antipsychotics, hypnotics, sedatives, anxiolytics, and antihistaminic drugs may be intensified; dosage reduction is recommended in such instances.

The metabolism of antidepressants is accelerated due to hepatic effects by oral contraceptives, phenytoin, carbamazepine and barbiturates. The metabolism of antidepressants is inhibited by cimetidine and some other antipsychotics.

In vitro drug metabolism studies suggest that there is a potential for drug interactions when Trazodone is given with potent CYP3A4 inhibitors such as erythromycin, ketoconazole, itraconazole, ritonavir, indinavir, and nefazodone. It is likely that potent CYP3A4 inhibitors may lead to substantial increases in trazodone plasma concentrations with the potential for adverse effects. Exposure to ritonavir during initiation or resumption of treatment in patients receiving Trazodone will increase the potential for excessive sedation, cardiovascular, and gastrointestinal effects. It has been confirmed in in- vivo-studies in healthy volunteers, that a ritonavir dose of 200 mg BID increased the plasma levels of Trazodone by greater than two-fold, leading to nausea, syncope and hypotension. If Trazodone is used with a potent CYP3A4 inhibitor, a lower dose of Trazodone should be considered. However, the co-administration of Trazodone and potent CYP3A4 inhibitors should be avoided where possible.

Carbamazepine reduced plasma concentrations of trazodone when coadministered. Concomitant use of carbamazepine 400 mg daily led to a decrease of plasma concentrations of Trazodone and its active metabolite m-chlorophenylpiperazine of 76 % and 60 %, respectively. Patients should be closely monitored to see if there is a need for an increased dose of Trazodone when taken with carbamazepine.

Trazodone may enhance the effects of muscle relaxants and volatile anaesthetics, and caution should be exercised in such instances. Similar considerations apply to combined administration with sedative and anti-depressant drugs, including alcohol. Trazodone intensifies the sedative effects of alcohol. Alcohol should be avoided during Trazodone therapy. Trazodone has been well tolerated in depressed schizophrenic patients receiving standard phenothiazine therapy and also in depressed parkinsonian patients receiving therapy with levodopa. Antidepressants can accelerate the metabolism of levodopa.

Tricyclic antidepressants: Concurrent administration should be avoided due to the risk of interaction. Serotonine syndrome and cardiovascular side effects should be bewared.

Fluoxetine: Rare cases have been reported of elevated Trazodone plasma levels and adverse effects when Trazodone had been combined with fluoxetine, a CYP1A2/2D6 inhibitor. The mechanism underlying a pharmacokinetic interaction is not fully understood. A pharmacodynamic interaction (serotonine syndrome) could not be excluded.

Possible interactions with monoamine oxidase inhibitors have occasionally been reported. Although some clinicians do give both concurrently, use of Trazodone with MAOIs, or within two weeks of stopping treatment with these compounds is not recommended. The giving of MAOIs within one week of stopping Trazodone is also not recommended.

Phenothiazines: Severe orthostatic hypotension has been observed in case of concomitant use of phenothiazines, like e.g. chlorpromazine, fluphenazine, levomepromazine, perphenazine.

Other

Concomitant use of Trazodone with drugs known to prolong the QT interval may increase the risk of ventricular arrhythmias, including torsade de pointes. Caution should be used when these drugs are coadministered with Trazodone.

Since Trazodone is only a very weak inhibitor of noradrenaline re-uptake and does not modify the blood pressure response to tyramine, interference with the hypotensive action of guanethidine-like compounds is unlikely. However, studies in laboratory animals suggest that Trazodone may inhibit most of the acute actions of clonidine. In the case of other types of antihypertensive drug, although no clinical interactions have been reported, the possibility of potentiation should be considered.

Undesirable effects may be more frequent when Trazodone is administered together with preparations containing Hypericum perforatum (St Johns wort).

There have been reports of changes in prothrombin time in patients concomitantly receiving trazodone and warfarin.

Concurrent use with Trazodone may result in elevated serum levels of digoxin or phenytoin. Monitoring of serum levels should be considered in these patients.

4.6 Pregnancy And Lactation

Pregnancy:

Data on a limited number (< 200) of exposed pregnancies indicate no adverse effects of Trazodone on pregnancy or on the health of the foetus/newborn child. To date, no other relevant epidemiological data are available. The safety of Trazodone in human pregnancy has not been established. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development at therapeutic doses. On basic principles, therefore, its use during the first trimester should be avoided.

Caution should be exercised when prescribing to pregnant women. When Trazodone is used until delivery, newborns should be monitored for the occurrence of withdrawal symptoms.

Lactation:

Limited data indicate that excretion of Trazodone in human breast milk is low, but levels of the active metabolite are not known. Due to the paucity of data, a decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Trazodone should be made taking into account the benefit of breast-feeding to the child and the benefit of Trazodone therapy to the woman.

4.7 Effects On Ability To Drive And Use Machines

Trazodone has minor or moderate influence on the ability to drive and use machines. As with all other drugs acting on the central nervous system, patients should be cautioned against the risks of driving or operating machinery until they are sure they are not affected by drowsiness, sedation, dizziness, confusional states, or blurred vision.

4.8 Undesirable Effects

Cases of suicidal ideation and suicidal behaviours have been reported during Trazodone therapy or early after treatment discontinuation (see section 4.4).

Trazodone has had no effect on arterial blood pCO₂ or pO₂ levels in patients with severe respiratory insufficiency due to chronic bronchial or pulmonary disease.

The following symptoms, some of which are commonly reported in cases of untreated depression, have also been recorded in patients receiving Trazodone therapy.

MedDRA System Organ Class	Frequency not known (cannot be estimated from the available data)
Blood and the lymphatic system disorders	Blood dyscrasias (including agranulocytosis, thrombocytopenia, eosinophilia, leucopenia and anaemia)
Immune system disorders	Allergic reactions
Endocrine disorders	Syndrome of Inappropriate Antidiuretic Hormone Secretion
Metabolism and nutrition disorders	Hyponatraemia1, weight loss, anorexia, increased appetite,
Psychiatric disorders	Suicidal ideation or suicidal behaviours2, confusional state, insomnia, disorientation, mania, anxiety, nervousness, agitation (very occasionally exacerbating to delirium), delusion, aggressive reaction, hallucinations, nightmares, libido decreased, withdrawal syndrome
Nervous system disorders	Serotonin syndrome, convulsion, neuroleptic malignant syndrome, dizziness, vertigo, headache, drowsiness3, restlessness, decreased alertness, tremor, blurred vision, memory disturbance, myoclonus, expressive aphasia, paraesthesia, dystonia, taste altered
Cardiac disorders	Cardiac arrhythmias4 (including Torsade de Pointes, palpitations, premature ventricular contractions, ventricular couplets, ventricular tachycardia), bradycardia, tachycardia, ECG abnormalities (QT prolongation)2
Vascular disorders	Ortostatic hypotension, hypertension, syncope
Respiratory, thoracic and mediastinal disorders	Nasal congestion, dyspnoea
Gastrointestinal disorders	Nausea, vomiting, dry mouth, constipation, diarrhoea, dyspepsia, stomach pain, gastroenteritis, increased salivation, paralytic ileus
Hepato-biliary disorders	Hepatic function abnormalities (including jaundice and hepatocellular damage)5 , cholestasis intrahepatic
Skin and subcutaneous tissue disorders	Skin rash, pruritus, hyperhidrosis
Musculoskeletal and connective tissue disorders	Pain in limb, back pain, myalgia, arthralgia
Renal and urinary disorders	Micturition disorderd
Reproductive system and breast disorders	Priapism6
General disorders and administration site conditions	Weakness, oedema, influenza-like symptoms, fatigue, chest pain, fever
Investigations	Elevated liver enzymes

¹ Fluid and electrolyte status should be monitored in symptomatic patients.

² See also Section 4.4.

³ Trazodone is a sedative antidepressant and drowsiness, sometimes experienced during the first days of treatment, usually disappears on continued therapy.

⁴ Studies in animals have shown that trazodone is less cardiotoxic than the tricyclic antidepressants, and clinical studies suggest that the drug may be less likely to cause cardiac arrhythmias in man. Clinical studies in patients with pre-existing cardiac disease indicate that trazodone may be arrhythmogenic in some patients in that population.

⁵ Adverse effects on hepatic function, sometimes severe, have been rarely reported. Should such effects occur, trazodone should be immediately discontinued.

⁶ See slso section 4.4.

4.9 Overdose

Features of toxicity

The most frequently reported reactions to overdose have included drowsiness, dizziness, nausea and vomiting. In more serious cases coma, tachycardia, hypotension, hyponatraemia, convulsions and respiratory failure have been reported. Cardiac features may include bradycardia, QT prolongation and torsade de pointes. Symptoms may appear 24 hours or more after overdose.

Overdoses of Trazodone in combination with other antidepressants may cause serotonin syndrome.

Management

There is no specific antidote to trazodone. Activated charcoal should be considered in adults who have ingested more than 1 g trazodone, or in children who have ingested more than 150 mg trazodone within 1 hour of presentation. Alternatively, in adults, gastric lavage may be considered within 1 hour of ingestion of a potentially life-threatening overdose.

Observe for at least 6 hours after ingestion (or 12 hours if a sustained release preparation has been taken). Monitor BP, pulse and Glasgow Coma Scale (GCS). Monitor oxygen saturation if GCS is reduced. Cardiac monitoring is appropriate in symptomatic patients.

Single brief convulsions do not require treatment. Control frequent or prolonged convulsions with intravenous diazepam (0.1-0.3 mg/kg body weight) or lorazepam (4 mg in an adult and 0.05 mg/kg in a child). If these measures do not control the fits, an intravenous infusion of phenytoin may be useful. Give oxygen and correct acid base and metabolic disturbances as required.

Treatment should be symptomatic and supportive in the case of hypotension and excessive sedation. If severe hypotension persists consider use of inotropes, eg dopamine or dobutamine

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC code: N06A X05. Other antidepressants.

Trazodone is a potent antidepressant. It also has anxiety reducing activity. Trazodone is a triazolopyridine derivative chemically unrelated to known tricyclic, tetracyclic and other antidepressant agents. It has negligible effect on noradrenaline re-uptake mechanisms. Whilst the mode of action of Trazodone is not known precisely, its antidepressant activity may concern noradrenergic potentiation by mechanisms other than uptake blockade. A central antiserotonin effect may account for the drug's anxiety reducing properties.

5.2 Pharmacokinetic Properties

Trazodone is rapidly absorbed from the gastro-intestinal tract and extensively metabolised. Paths of metabolism of trazodone include n-oxidation and hydroxylation. The metabolic m-chlorophenylpiperazine is active. Trazodone is excreted in the urine almost entirely in the form of its metabolites, either in free or in conjugated form. The elimination of Trazodone is biphasic, with a terminal elimination half-life of 5 to 13 hours. Trazodone is excreted in breast milk.

There was an approximate two-fold increase in terminal phase half-life and significantly higher plasma concentrations of trazodone in 10 subjects aged 65 to 74 years compared with 12 subjects aged 23 to 30 years following a 100mg dose of trazodone. It was suggested that there is an age-related reduction in the hepatic metabolism of trazodone.

In vitro studies in human liver microsomes show that trazodone is metabolised by cytochrome P4503A4 (CYP3A4) to form m-chlorophenylpiperazine. Whilst significant, the role of this pathway in the total clearance of trazodone in vivo has not been fully determined.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose

Magnesium stearate

Gelatin

Titanium dioxide E171

Erythrosine E127

Indigo Carmine E132

Red iron oxide E172

Yellow iron oxide E172

Ink (1028 (S-1-27794) or 1014 (SW-9008) Black)

6.2 Incompatibilities

None stated.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

Blister packs: Store below 30ºC in a dry place.

Glass bottles and securitainers: Store below 30ºC.

6.5 Nature And Contents Of Container

i) Amber glass bottles with jay-cap closures: contents 100 capsules.

ii) PVdC coated 250μm PVC blisters sealed with 20μm aluminium foil: contents 56 and 100 capsules.

iii) Securitainers: contents 1000 capsules.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8. Marketing Authorisation Number(S)

PL 04425/0180

9. Date Of First Authorisation/Renewal Of The Authorisation

26 August 2009

10. Date Of Revision Of The Text

27/09/2010

LEGAL STATUS

POM

Kwells 300 microgram tablets

1. Name Of The Medicinal Product

Kwells 300 microgram tablets

2. Qualitative And Quantitative Composition

Hyoscine Hydrobromide 300 microgram

For excipients, see section 6.1

3. Pharmaceutical Form

Tablet

Small pink circular, flat faced tablets with bevelled edges. One face is bisected by a score line and the other is plain.

4. Clinical Particulars

4.1 Therapeutic Indications

For the prevention of travel sickness.

4.2 Posology And Method Of Administration

Tablets to be sucked, chewed or swallowed

Adults:

1 tablet every 6 hours if required. Do not take more than 3 tablets in 24 hours.

Elderly

There is no special dosage regimen for the elderly and as such caution should be exercised

Children

Children over 10: ½-1 tablet every 6 hours if required. Do not take more than 1½-3 tablets in 24 hours.

Tablets to be taken up to 30 minutes before the start of the journey to prevent travel sickness, or at the onset of nausea.

4.3 Contraindications

Prostatic enlargement, paralytic ileus, pyloric stenosis, glaucoma and myasthenia gravis.

In addition, Kwells should not be given to patients with a known sensitivity to hyoscine hydrobromide or any other component of the product.

4.4 Special Warnings And Precautions For Use

The elderly and patients under medical care (in particular those at risk of acute urinary retention, or with cardiovascular, metabolic, gastrointestinal, liver or renal disease, or suffering from CNS disorders such as seizures) should consult a doctor before taking this product.

In patients with ulcerative colitis its use may lead to ileus or megacolon.

Antimuscarinics should be used with caution in persons with Down's Syndrome.

Caution is advisable in patients with diarrhoea.

Hyperthermia can occur at high ambient temperatures due to decreased sweating, therefore, Kwells should be used with caution in patients with fever.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The effects of hyoscine may be enhanced by other drugs with anticholinergic properties (including amantadine, some antihistamines, phenothiazine antipsychotics and tricyclic antidepressants), therefore, combining these drugs with hyoscine should be avoided.

There may be an increased risk of side effects when given with MAOIs due to inhibition of drug-metabolising enzymes.

The sedative effect of Kwells may be enhanced with alcohol or CNS depressants.

The reduction in gastric motility caused by Kwells may also affect the absorption of other drugs. There is an antagonism of effect of domperidone and metoclopramide on gastro-intestinal activity.

There could be a reduced effect of sublingual nitrate tablets due to the failure to dissolve properly under the tongue owing to dry mouth.

4.6 Pregnancy And Lactation

The safety of this medicine in pregnancy has not been established. It should only be used during pregnancy, particularly in the first trimester, if the expected benefit to the mother outweighs any potential risk to the developing foetus and on advice of a physician.

Caution is required during lactation as small amounts of this medicine may pass into breast milk.

4.7 Effects On Ability To Drive And Use Machines

May cause drowsiness. If affected do not drive or operate machinery.

4.8 Undesirable Effects

The listed adverse drug reactions are based on spontaneous reports, thus an organization according to CIOMS II categories of frequency is not pertinent.

General: hyperthermia at high temperatures due to decreased sweating.

Eye disorders: blurred vision, mydriasis.

Gastrointestinal disorders: dry mouth.

Immune system disorders: allergic reaction and anaphylactic reaction. Hypersensitivity reactions with respective laboratory and clinical manifestations, including asthma syndrome, mild to moderate reactions affecting skin, respiratory tract, gastrointestinal tract, and cardiovascular system, and symptoms such as rash, urticaria, oedema, pruritus, cardio-respiratory distress, have been reported.

Nervous system disorders: drowsiness, dizziness, sedation and somnolence are commonly reported. Central nervous system stimulation including restlessness, hallucinations and confusion, have been less frequently reported following the administration of hyoscine. There have been rare reports of an increase in seizure frequency in epileptic patients (the same caution for this patient population is included in Section 4.4).

4.9 Overdose

The symptoms of overdosage are tachycardia, arrhythmia, blurring of vision and photophobia, and urinary retention. Drowsiness is usual but paradoxical stimulation with hallucinations may occur.

Treatment: gastric lavage or induced emesis and symptomatic treatment.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Hyoscine hydrobromide is thought to act as an anticholinergic agent by both cutting off stimuli to the vestibular apparatus and also by acting directly on the vomiting centre.

5.2 Pharmacokinetic Properties

Hyoscine hydrobromide is readily absorbed from the gastro-intestinal tract, and in circulation is bound to plasma proteins. It is effective for about 4 hours and is almost entirely metabolised in the body.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Mannitol

Potato Starch

Gelatin Powder

Aluminium Stearate

Saccharin Sodium

Ferric Oxide

Purified Water (not detectable)

6.2 Incompatibilities

None known.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

Do not store above 25 °C.

6.5 Nature And Contents Of Container

1. Strip packs formed from 0.03mm soft-tempered aluminium coated with polyethylene.

a. Two strips of six tablets in cardboard carton.

b. One strip of twelve tablets in cardboard carton.

c. Strip of two tablets stapled into a cardboard cover.

2. Blister packs formed from 20um hard-tempered aluminium foil with either 250um opaque, white PVC or 250um opaque, white PVC coated with 40gsm PVDC

a. Two strips of six tablets in cardboard carton.

b. One strip of twelve tablets in cardboard carton

c. Strip of two tablets stapled into a cardboard cover.

Pack sizes: 2, 12

6.6 Special Precautions For Disposal And Other Handling

No special precautions necessary.

Administrative Data

7. Marketing Authorisation Holder

Bayer plc

Bayer House

Newbury

Berkshire

RG14 1JA

United Kingdom

8. Marketing Authorisation Number(S)

PL 0010/0329

9. Date Of First Authorisation/Renewal Of The Authorisation

12/10/2005

10. Date Of Revision Of The Text

19/11/2007

Vorinostat

Pronunciation: vor-IN-oh-stat
Generic Name: Vorinostat
Brand Name: Zolinza

Vorinostat is used for:

Treating certain patients with skin symptoms caused by a type of cancer (cutaneous T-cell lymphoma [CTCL]).

Vorinostat is a histone deacetylase (HDAC) inhibitor. It works by blocking the growth of some cancer cells.

Do NOT use Vorinostat if:

• you are allergic to any ingredient in Vorinostat


• you have severe liver problems

Contact your doctor or health care provider right away if any of these apply to you.

Before using Vorinostat:

Some medical conditions may interact with Vorinostat. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you are dehydrated or have severe or persistent nausea, vomiting, or diarrhea


• if you have low blood magnesium or potassium levels, anemia, or low blood platelet levels


• if you have diabetes or high blood sugar, or are at risk for diabetes


• if you have a history of kidney or liver problems or blood clots (eg, in the lungs or legs)

Some MEDICINES MAY INTERACT with Vorinostat. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Valproic acid because the risk of low blood platelet levels, unusual bruising or bleeding, and serious stomach or bowel bleeding may be increased


• Anticoagulants (eg, warfarin) because the risk of its side effects may be increased by Vorinostat

This may not be a complete list of all interactions that may occur. Ask your health care provider if Vorinostat may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Vorinostat:

Use Vorinostat as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Vorinostat. Talk to your pharmacist if you have questions about this information.


• Take Vorinostat by mouth with food.


• Swallow Vorinostat whole. Do not open, break, crush, or chew before swallowing.


• If the capsule is accidentally crushed or broken, do NOT touch the powder. If you get the powder on your skin or in your eyes, wash them immediately with water. Contact your doctor right away.


• Drinking extra fluids (at least eight 8 oz glasses of liquid per day) while you are taking Vorinostat is recommended. Check with your doctor for instructions.


• Be sure you know how to properly handle and dispose of Vorinostat. Contact your doctor if you have questions.


• If you miss a dose of Vorinostat, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Vorinostat.

Important safety information:

• Vorinostat may cause dizziness or fatigue. These effects may be worse if you take it with alcohol or certain medicines. Use Vorinostat with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• If vomiting or diarrhea occurs, you will need to take care not to become dehydrated. Contact your doctor for instructions.


• Vorinostat may reduce the number of clot-forming cells (platelets) in your blood. Avoid activities that may cause bruising or injury. Tell your doctor if you have unusual bruising or bleeding. Tell your doctor if you have dark, tarry, or bloody stools.


• Vorinostat may raise your blood sugar. High blood sugar may make you feel confused, drowsy, or thirsty. It can also make you flush, breathe faster, or have a fruit-like breath odor. If these symptoms occur, tell your doctor right away.


• Diabetes patients - Vorinostat may affect your blood sugar. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.


• Lab tests, including complete blood cell counts, blood electrolyte levels, and blood glucose levels, may be performed while you use Vorinostat. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Vorinostat should be used with extreme caution in CHILDREN younger than 18 years old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Vorinostat has been shown to cause harm to the fetus. If you think you may be pregnant, contact your doctor. You will need to discuss the benefits and risks of using Vorinostat while you are pregnant. It is not known if Vorinostat is found in breast milk. Do not breast-feed while taking Vorinostat.

Possible side effects of Vorinostat:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; cough; diarrhea; dizziness; dry mouth; fatigue; hair loss; headache; loss of appetite; muscle aches; nausea; taste changes; vomiting; weight loss.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); black, tarry, or bloody stools; calf or leg pain, swelling, redness, or warmth to the touch; chest pain; coughing up blood; fainting; fast or irregular heartbeat; muscle pain or spasms; severe or persistent nausea, vomiting, or diarrhea; shortness of breath; swelling of the hands, ankles, or feet; symptoms of high blood sugar (eg, increased urination, thirst, or hunger; confusion; drowsiness; flushing; fast breathing; fruit-like breath odor); symptoms of infection (eg, fever, chills, persistent or severe cough, or sore throat); unusual bleeding or bruising; unusual anxiety or sweating; unusual weakness or tiredness; vomit that looks like coffee grounds.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Vorinostat side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Vorinostat:

Store Vorinostat at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Vorinostat out of the reach of children and away from pets.

General information:

• If you have any questions about Vorinostat, please talk with your doctor, pharmacist, or other health care provider.


• Vorinostat is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Vorinostat. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Vorinostat resources

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

• Vorinostat Professional Patient Advice (Wolters Kluwer)


• Vorinostat Monograph (AHFS DI)


• vorinostat Advanced Consumer (Micromedex) - Includes Dosage Information


• Zolinza Prescribing Information (FDA)


• Zolinza Consumer Overview

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• Cutaneous T-cell Lymphoma

Savlon Bites & Stings Pain Relief Gel

1. Name Of The Medicinal Product

Savlon Bites & Stings Pain Relief Gel

2. Qualitative And Quantitative Composition

Active ingredients:

Lidocaine Hydrochloride 2.0% w/w

Zinc Sulphate 1.0% w/w

Cetrimide 0.5% w/w

For Excipients, see section 6.1

3. Pharmaceutical Form

Gel

Colourless, viscous gel with a characteristic menthol odour

4. Clinical Particulars

4.1 Therapeutic Indications

For the symptomatic relief of pain, itching, irritation, and for antiseptic protection. For use in insect bites and stings, and skin reactions such as nettle rash, caused by contact with plants.

4.2 Posology And Method Of Administration

Adults and children over 12 years:

Apply a small amount to the affected area with a fingertip.

Repeat if required up to 3-4 times daily.

Children under 12 years:

Not recommended (insufficient data available).

Route of administration:

For cutaneous use

4.3 Contraindications

Patients with a known hypersensitivity to any ingredient should not use the product

4.4 Special Warnings And Precautions For Use

Contact with the eyes should be avoided.

For external use only.

Not suitable for animal bites.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No known interactions with other drugs.

4.6 Pregnancy And Lactation

There are no known adverse effects in normal use of this product in pregnancy and lactation.

Exposure to systemically absorbed lidocaine from the product is low. The active ingredients have been in use for many years and no special precautions are considered necessary.

4.7 Effects On Ability To Drive And Use Machines

There are no known adverse effects on driving and using machinery.

The active ingredients have been in use for many years at much higher levels of exposure and no precautions are considered necessary for use in driving and using machinery.

4.8 Undesirable Effects

Rarely, skin irritation and sensitisation may occur.

4.9 Overdose

Overdosage effects are unlikely as the systemic dose from this topical product is likely to be very low.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Three pharmacological effects are provided:

Lidocaine hydrochloride is a local anaesthetic of the amide type which is widely used for local application to the skin and mucous membranes. It produces surface anaesthesia by diminishing or preventing the conduction of sensory nerve impulses.

Cetrimide is a quaternary ammonium antiseptic. As well as having emulsifying and detergent properties, it has antibacterial activity against gram-positive organisms and to a lesser extent against some gram-negative organisms.

Zinc sulphate has astringent and soothing properties.

5.2 Pharmacokinetic Properties

The product is intended for local action. Lidocaine hydrochloride is well-absorbed through mucous membranes and more slowly absorbed through intact skin.

5.3 Preclinical Safety Data

No relevant information is available other than that given in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Hydroxyethylmethylcellulose

Polysorbate 20

Nonoxynol 9

Propylene Glycol

Levomenthol

Purified Water

6.2 Incompatibilities

None known

6.3 Shelf Life

36 months.

Shelf life following opening of the tube: 3 months.

6.4 Special Precautions For Storage

Do not store above 30°C

6.5 Nature And Contents Of Container

Laminated tube consisting of aluminium foil coated internally and externally with low density polyethylene or high density polyethylene.

Pack size: 3g, 20g

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Novartis Consumer Health UK Ltd

Wimblehurst Road

Horsham

RH12 5AB

West Sussex

Trading Style: Novartis Consumer Health

8. Marketing Authorisation Number(S)

PL 00030/0161

9. Date Of First Authorisation/Renewal Of The Authorisation

15 February 2001

10. Date Of Revision Of The Text

31 October 2006

Legal category: GSL

Zelnorm

Pronunciation: teg-a-SER-od
Generic Name: Tegaserod
Brand Name: Zelnorm

Zelnorm is used for:

Short term treatment of irritable bowel syndrome (IBS) in women who have constipation as their main symptom. It is also used for treating certain men and women who have a type of chronic constipation. It may also be used for other conditions as determined by your doctor.

Zelnorm is a selective serotonin receptor agonist. It works on the nerves of the bowel to improve bowel function. This helps you to have more normal stools.

Do NOT use Zelnorm if:

• you are allergic to any ingredient in Zelnorm


• you have moderate to severe liver problems or severe kidney problems


• you have a history of certain bile duct or gallbladder problems, blockage of the bowel, or abdominal adhesions


• you have diarrhea or you have diarrhea often

Contact your doctor or health care provider right away if any of these apply to you.

Before using Zelnorm:

Some medical conditions may interact with Zelnorm. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have a history of certain severe bowel problems (eg, ischemic colitis) or gallbladder, liver, or kidney problems


• if you have low blood pressure or are dehydrated

Some MEDICINES MAY INTERACT with Zelnorm. However, no specific interactions with Zelnorm are known at this time.

Ask your health care provider if Zelnorm may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Zelnorm:

Use Zelnorm as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Zelnorm. Talk to your pharmacist if you have questions about this information.


• Take Zelnorm by mouth on an empty stomach, shortly before you eat a meal, unless your doctor tells you otherwise.


• If you miss a dose of Zelnorm, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Zelnorm.

Important safety information:

• Zelnorm may cause dizziness. This effect may be worse if you take it with alcohol or certain medicines. Use Zelnorm with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Use Zelnorm with caution in the ELDERLY; they may be more sensitive to its effects, especially diarrhea.


• Zelnorm should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Zelnorm while you are pregnant. It is not known if Zelnorm is found in the breast milk. Do not breast-feed while taking Zelnorm.

Possible side effects of Zelnorm:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Diarrhea; headache.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bloody stools; diarrhea with severe cramping; fainting; new or worsening stomach pain; rectal bleeding; severe or persistent diarrhea or dizziness.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Zelnorm side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include severe or persistent diarrhea, headache, or nausea; stomach pain; vomiting.

Proper storage of Zelnorm:

Store Zelnorm at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Zelnorm out of the reach of children and away from pets.

General information:

• If you have any questions about Zelnorm, please talk with your doctor, pharmacist, or other health care provider.


• Zelnorm is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is summary only. It does not contain all information about Zelnorm. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Zelnorm resources

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

• Zelnorm Prescribing Information (FDA)


• Zelnorm Monograph (AHFS DI)


• Zelnorm Advanced Consumer (Micromedex) - Includes Dosage Information


• Zelnorm Consumer Overview

Compare Zelnorm with other medications

• Constipation, Chronic
• Irritable Bowel Syndrome

Azilect

FULL PRESCRIBING INFORMATION

Azilect® (rasagiline tablets)

Indications and Usage for Azilect

Azilect (rasagiline tablets) is indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa.

The effectiveness of Azilect was demonstrated in patients with early Parkinson's disease who were receiving Azilect as monotherapy and who were not receiving any concomitant dopaminergic therapy. The effectiveness of Azilect as adjunct therapy was demonstrated in patients with Parkinson's disease who were treated with levodopa.

Azilect Dosage and Administration

 Azilect is a selective inhibitor of monoamine oxidase (MAO)-B at recommended doses of 0.5 or 1 mg daily. Dietary tyramine restriction is not ordinarily required with recommended doses of Azilect. However, certain foods (e.g., aged cheeses, such as Stilton cheese) may contain very high amounts (i.e., > 150 mg) of tyramine and could potentially cause a hypertensive "cheese" reaction in patients taking Azilect even at the recommended dose due to mild increased sensitivity to tyramine. The selectivity for inhibiting MAO-B diminishes in a dose-related manner as the dose is progressively increased above the recommended daily dose [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3, and Information for Patients (17.3))].

Monotherapy

The recommended Azilect dose for the treatment of Parkinson's disease patients is 1 mg administered orally once daily.

Adjunctive Therapy

The recommended initial dose is 0.5 mg administered orally once daily. If a sufficient clinical response is not achieved, the dose may be increased to 1 mg administered once daily.

Change of Levodopa Dose in Adjunct Therapy

When Azilect is used in combination with levodopa, a reduction of the levodopa dosage may be considered based upon individual response. During the controlled trials of Azilect as adjunct therapy to levodopa, levodopa dosage was reduced in some patients. In clinical studies, dosage reduction of levodopa was allowed within the first 6 weeks if dopaminergic side effects, including dyskinesia and hallucinations, emerged. In Study 1, levodopa dosage reduction occurred in 8% of patients in the placebo group and in 16% and 17% of patients in the 0.5 mg/day and 1 mg/day rasagiline groups, respectively. In those patients who had levodopa dosage reduced, the dose was reduced on average by about 7%, 9%, and 13% in the placebo, 0.5 mg/day, and 1 mg/day groups, respectively. In Study 2, levodopa dosage reduction occurred in 6% of patients in the placebo group and in 9% in the rasagiline 1 mg/day group. In patients who had their levodopa dosage reduced, the dose was reduced on average by about 13% and 11% in the placebo and the rasagiline groups, respectively.

Patients with Hepatic Impairment

Azilect plasma concentrations will increase in patients with hepatic impairment. Patients with mild hepatic impairment should use 0.5 mg daily of Azilect. Azilect should not be used in patients with moderate or severe hepatic impairment [see Warnings and Precautions (5.3), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

Patients with Renal Impairment

Dose adjustment of Azilect is not required for patients with mild or moderate renal impairment because Azilect plasma concentrations are not increased in patients with moderate renal impairment. Rasagiline has not been studied in patients with severe renal impairment.

Patients Taking Ciprofloxacin or Other CYP1A2 Inhibitors

Rasagiline plasma concentrations are expected to double in patients taking concomitant ciprofloxacin and other CYP1A2 inhibitors. Therefore, patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should use 0.5 mg daily of Azilect [see Warnings and Precautions (5.2), Drug Interactions (7.7), and Clinical Pharmacology (12.3)].

Dosage Forms and Strengths

Azilect 0.5 mg Tablets: White to off-white, round, flat, beveled tablets, debossed with "GIL 0.5" on one side and plain on the other side containing, as the active ingredient, rasagiline mesylate equivalent to 0.5 mg of rasagiline base.

Azilect 1 mg Tablets: White to off-white, round, flat, beveled tablets, debossed with "GIL 1" on one side and plain on the other side containing, as the active ingredient, rasagiline mesylate equivalent to 1 mg of rasagiline base.

Contraindications

Meperidine and Certain Other Analgesics

 Azilect is contraindicated for use with meperidine. Serious adverse reactions have been precipitated with concomitant use of meperidine (e.g., Demerol and other tradenames) and MAO inhibitors (MAOIs) including selective MAO-B inhibitors. These adverse reactions are often described as "serotonin syndrome", a potentially serious condition, which can result in death. Typical clinical signs and symptoms include behavioral and cognitive/mental status changes (e.g., confusion, hypomania, hallucinations, agitation, delirium, headache, and coma), autonomic effects (e.g., syncope, shivering, sweating, high fever/hyperthermia, hypertension, hypotension, tachycardia, nausea, diarrhea), and somatic effects (e.g., muscular rigidity, myoclonus, muscle twitching, hyperreflexia manifested by clonus, and tremor). At least 14 days should elapse between discontinuation of Azilect and initiation of treatment with meperidine.

For similar reasons, Azilect should not be administered with the analgesic agents tramadol, methadone, and propoxyphene.

In the post-marketing period, serotonin syndrome has been reported in a patient erroneously treated with a higher than recommended dose of Azilect (4 mg daily) and tramadol.

Other Drugs

Azilect should not be used with the antitussive agent dextromethorphan. The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior. Azilect is also contraindicated for use with St. John's wort, and cyclobenzaprine (a tricyclic muscle relaxant).

MAO Inhibitors

Azilect should not be administered along with any other MAO inhibitor (selective or non-selective) because of the increased risk of non-selective MAO inhibition that may lead to a hypertensive crisis. At least 14 days should elapse between discontinuation of Azilect and initiation of treatment with any MAO inhibitor.

Warnings and Precautions

Coadministration with Antidepressants

 Severe CNS toxicity associated with hyperpyrexia has been reported with the combined treatment of an antidepressant (e.g., selective serotonin reuptake inhibitors-SSRIs, serotonin-norepinephrine reuptake inhibitors-SNRIs, tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants) and a non-selective MAOI (e.g., phenelzine, tranylcypromine) or selective MAO-B inhibitors, such as selegiline (Eldepryl) and rasagiline (Azilect). These adverse reactions are often described as "serotonin syndrome" which can result in death. In the post-marketing period, non-fatal cases of serotonin syndrome have been reported in patients treated with antidepressants concomitantly with Azilect.

The symptoms of serotonin syndrome have included behavioral and cognitive/mental status changes (e.g., confusion, hypomania, hallucinations, agitation, delirium, headache, and coma), autonomic effects (e.g., syncope, shivering, sweating, high fever/hyperthermia, hypertension, tachycardia, nausea, diarrhea), and somatic effects (e.g., muscular rigidity, myoclonus, muscle twitching, hyperreflexia manifested by clonus, and tremor).

Azilect clinical trials did not allow concomitant use of fluoxetine or fluvoxamine with Azilect, but the following antidepressants and doses were allowed in the Azilect trials: amitriptyline ≤ 50 mg/daily, trazodone ≤ 100 mg/daily, citalopram ≤ 20 mg/daily, sertraline ≤ 100 mg/daily and paroxetine ≤ 30 mg/daily.

Although a small number of rasagiline-treated patients were concomitantly exposed to antidepressants (tricyclics n=115; SSRIs n=141), the exposure, both in dose and number of subjects, was not adequate to rule out the possibility of an untoward reaction from combining these agents. Furthermore, because the mechanisms of these reactions are not fully understood, it seems prudent, in general, to avoid the combination of Azilect with any antidepressant. At least 14 days should elapse between discontinuation of Azilect and initiation of treatment with a SSRI, SNRI, tricyclic, tetracyclic, or triazolopyridine antidepressant. Because of the long half lives of certain antidepressants (e.g., fluoxetine and its active metabolite), at least five weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) should elapse between discontinuation of fluoxetine and initiation of Azilect [see Drug Interactions (7.5)].

Ciprofloxacin and Other CYP1A2 Inhibitors

Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant ciprofloxacin and other CYP1A2 inhibitors [see Dosage and Administration (2.5), Drug Interactions (7.7), and Clinical Pharmacology (12.3)].

Hepatic Impairment

Rasagiline plasma concentration may increase in patients with mild (up to 2 fold, Child-Pugh score 5-6), moderate (up to 7 fold, Child-Pugh score 7-9), and severe (Child-Pugh score 10-15) hepatic impairment. Patients with mild hepatic impairment should be given the dose of 0.5 mg/day. Azilect should not be used in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Risk for Hypertensive Crisis and Nonselective Monoamine Oxidase Inhibition Above The Recommended Doses

Azilect is a selective inhibitor of monoamine oxidase (MAO)-B at the recommended doses of 0.5 or 1 mg daily. Azilect should not be used at daily doses exceeding 1 mg/day (or 0.5 mg/day for patients with mild hepatic impairment or in patients using concomitant ciprofloxacin or another CYP1A2 inhibitor) because of the risks of hypertensive crisis and other adverse reactions associated with nonselective inhibition of MAO [see Dosage and Administration (2), Drug Interactions (7.9), and Clinical Pharmacology (12.3)].

Dietary tyramine restriction is not ordinarily required with ingestion of most foods and beverages that may contain tyramine, during treatment with recommended doses of Azilect. However, certain foods (e.g., aged cheeses, such as Stilton cheese) may contain very high amounts (i.e., > 150 mg) of tyramine and could potentially cause a hypertensive "cheese" reaction in patients taking Azilect even at the recommended doses due to mild increased sensitivity to tyramine. Patients should be advised to avoid foods (e.g., aged cheese) containing a very large amount of tyramine while taking recommended doses of Azilect because of the potential for large increases in blood pressure. Selectivity for inhibiting MAO-B diminishes in a dose-related manner as the dose is progressively increased above the recommended daily doses.

There were no cases of hypertensive crisis in the clinical development program associated with 1 mg daily rasagiline treatment, in which most patients did not follow dietary tyramine restriction.

Rare cases of hypertensive crisis have been reported in the post-marketing period in patients after ingesting unknown amounts of tyramine-rich foods while taking recommended doses of Azilect.

Melanoma

Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Dyskinesia

When used as an adjunct to levodopa, Azilect may cause dyskinesia or potentiate dopaminergic side effects and exacerbate pre-existing dyskinesia (treatment-emergent dyskinesia occurred in about 18% of patients treated with 0.5 mg or 1 mg rasagiline as an adjunct to levodopa, and 10% of patients who received placebo as an adjunct to levodopa). Decreasing the dose of levodopa may ameliorate this side effect.

Lowering of Blood Pressure and Postural/Orthostatic Hypotension

In placebo controlled studies of Azilect given in combination with levodopa, the incidence of postural hypotension consisting of a systolic blood pressure decrease (≥ 30 mm Hg) or a diastolic blood pressure decrease (≥ 20 mm Hg) after standing was 13.4 % with Azilect (1 mg/day) compared to 8.5 % with placebo.

At the 1 mg dose, the frequency of orthostatic hypotension at any time during the study was approximately 44 % for Azilect vs 33% for placebo for mild to moderate systolic blood pressure decrements (≥ 20 mm Hg), 40 % for Azilect vs 33 % for placebo for mild to moderate diastolic blood pressure decrements (≥ 10 mm Hg), 7 % for Azilect vs 3 % for placebo for severe systolic blood pressure decrements (≥ 40 mm Hg), and 9 % for Azilect vs 6 % for placebo for severe diastolic blood pressure decrements (≥ 20 mm Hg). There was also an increased risk for some of these abnormalities at the lower 0.5 mg daily dose and for an individual patient having mild to moderate or severe postural hypotension for both systolic and diastolic blood pressure.

Clinical trial data further suggest that postural hypotension occurs most frequently in the first two months of Azilect treatment and tends to decrease over time.

Some patients treated with Azilect experienced a mildly increased risk for significant decreases in blood pressure unrelated to standing but while supine.

The risk for post-treatment hypotension (e.g., systolic < 90 or diastolic < 50 mm Hg) combined with a significant decrease from baseline (e.g., systolic > 30 or diastolic > 20 mm Hg) was higher for Azilect 1 mg (3.2 %) compared to placebo (1.3 %).

There was no clear increased risk for lowering of blood pressure or postural hypotension associated with Azilect 1 mg/day as monotherapy.

When used as an adjunct to levodopa, postural hypotension was also reported as an adverse reaction in approximately 6% of patients treated with 0.5 mg rasagiline, 9% of patients treated with 1 mg rasagiline and 3% of patients treated with placebo. Postural hypotension led to drug discontinuation and premature withdrawal from clinical trials in one (0.7%) patient treated with rasagiline 1 mg/day, no patients treated with rasagiline 0.5 mg/day and no placebo-treated patients.

Elevation of Blood Pressure

In studies in which Azilect (1 mg/day) was given in conjunction with levodopa, Azilect produced an increased incidence of a significant, high blood pressure (e.g., systolic > 180 or diastolic > 100 mm Hg) of 4% compared to 3% for placebo.

The risk for developing post-treatment high blood pressure (e.g., systolic > 180 or diastolic >100 mm Hg) combined with a significant increase from baseline (e.g., systolic > 30 or diastolic > 20 mm Hg) was higher for Azilect (2 %) compared to placebo (1 %).

There was no increased frequency of the incidence of hypertension as an adverse reaction in the adjunctive treatment pivotal trials for Azilect treatment vs placebo.

There was no observed increased risk for increasing blood pressure or high blood pressure (based upon various measurements and analyses) or for the development of hypertension as an adverse reaction in the monotherapy study for 1 mg daily Azilect treatment (vs placebo).

Hallucinations / Psychotic-Like Behavior

In the monotherapy study, hallucinations were reported as an adverse event in 1.3% of patients treated with 1 mg rasagiline and in 0.7% of patients treated with placebo. In the monotherapy trial, hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 1.3% of the 1 mg rasagiline-treated patients and in none of the placebo-treated patients.

When used as an adjunct to levodopa, hallucinations were reported as an adverse reaction in approximately 5% of patients treated with 0.5 mg/day Azilect, 4% of patients treated with 1 mg/day Azilect and 3% of patients treated with placebo. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in about 1% of patients treated with 0.5 mg/day or 1 mg/day rasagiline and none of the placebo-treated patients.

Patients should be informed of the possibility of developing hallucinations and instructed to report them to their health care provider promptly should they develop.

Patients with a major psychotic disorder should ordinarily not be treated with Azilect because of the risk of exacerbating the psychosis with an increase in central dopaminergic tone. In addition, many treatments for psychosis that decrease in central dopaminergic tone may decrease the effectiveness of Azilect.

Azilect administration may cause or exacerbate psychotic-like behavior based upon post-marketing reports. This adverse reaction has been reported with many anti-Parkinsonian drugs that increase central dopaminergic tone. This abnormal behavior has been exhibited by one or more of a variety of manifestations including paranoia, confusional state/confusion, psychotic disorder, agitation, delusion, and hallucinations.

Withdrawal-Emergent Hyperpyrexia and Confusion

A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone. [see Dosage and Administration (2.2)].

Withdrawal emergent hyperpyrexia was not reported in the Azilect clinical development program.

Laboratory Tests

No specific laboratory tests are required for the treatment of patients on Azilect.

Adverse Reactions

Clinical Studies Experience

During the clinical development of Azilect, 1361 Parkinson's disease patients received rasagiline as initial monotherapy or as adjunct therapy to levodopa. As these two populations differ, not only in the adjunct use of levodopa during rasagiline treatment, but also in the severity and duration of their disease, they may have differential risks for various adverse reactions. Therefore, most of the adverse reactions data in this section are presented separately for each population.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates of adverse reactions observed in practice.

Patients Receiving Azilect as Initial Monotherapy Treatment

Adverse Reactions Leading to Discontinuation in Controlled Clinical Studies

In the double-blind, placebo-controlled trials conducted in patients receiving Azilect as monotherapy, approximately 5% of the 149 patients treated with rasagiline discontinued treatment due to adverse reactions compared to 2% of the 151 patients who received placebo.

The only adverse reaction that led to the discontinuation of more than one patient was hallucinations.

Adverse Reaction Incidence in Controlled Clinical Studies

The most commonly observed adverse reactions were those in which the treatment difference for the incidence in Azilect-treated patients was ≥ 3 % greater than the incidence in the placebo-treated patients and included flu syndrome, arthralgia, depression, and dyspepsia. Table 1 lists treatment-emergent adverse reactions that occurred in ≥ 2% of patients receiving Azilect as monotherapy participating in the double-blind, placebo-controlled trial and were numerically more frequent than in the placebo group.

Table 1. Treatment-Emergent* Adverse Reactions in Azilect 1 mg-Treated Monotherapy Patients

Placebo-Controlled Studies Without Levodopa Treatment	Azilect 1 mg (N=149)	Placebo (N=151)
	% of Patients	% of Patients
* Incidence ≥ 2% in Azilect 1 mg group and numerically more frequent than in placebo group
Headache	14	12
Arthralgia	7	4
Dyspepsia	7	4
Depression	5	2
Fall	5	3
Flu syndrome	5	1
Conjunctivitis	3	1
Fever	3	1
Gastroenteritis	3	1
Rhinitis	3	1
Arthritis	2	1
Ecchymosis	2	0
Malaise	2	0
Neck Pain	2	0
Paresthesia	2	1
Vertigo	2	1

Other events of potential clinical importance reported by 1% or more of patients receiving Azilect as monotherapy, and at least as frequent as in the placebo group, in descending order of frequency include: dizziness, diarrhea, chest pain, albuminuria, allergic reaction, alopecia, angina pectoris, anorexia, asthma, hallucinations, impotence, leukopenia, libido decreased, liver function tests abnormal, skin carcinoma, syncope, vesiculobullous rash, vomiting.

There were no significant differences in the safety profile based on age or gender.

Patients Receiving Azilect as Adjunct to Levodopa Therapy

Adverse Reactions Leading to Discontinuation in Controlled Clinical Studies

In a double-blind, placebo-controlled trial (Study 1) conducted in patients treated with Azilect as adjunct to levodopa therapy, approximately 9% of the 164 patients treated with Azilect 0.5 mg/day and 7% of the 149 patients treated with Azilect 1 mg/day discontinued treatment due to adverse reactions compared to 6% of the 159 patients who received placebo. The adverse reactions that led to discontinuation of more than one rasagiline-treated patient were: diarrhea, weight loss, hallucination, and rash. Adverse event reporting was considered more reliable for Study 1 than for the second controlled trial (Study 2); therefore only the adverse event data from Study 1 are presented in this section of labeling.

Adverse Reactions: Incidence in Controlled Clinical Studies

The most commonly observed adverse reactions were those in which the treatment difference for the incidence in Azilect-treated patients (n=149) was ≥ 3 % greater than the incidence in the placebo-treated patients (n=159) and included dyskinesia, accidental injury, weight loss, postural hypotension, vomiting, anorexia, arthralgia, abdominal pain, nausea, constipation, dry mouth, rash, abnormal dreams, and fall.

Table 2 lists treatment-emergent adverse reactions that occurred in ≥ 2% of patients treated with Azilect 1 mg/day as adjunct to levodopa therapy participating in the double-blind, placebo-controlled trial (Study 1) and that were numerically more frequent than the placebo group. The table also shows the rates for the 0.5 mg group in Study 1.

Table 2. Incidence of Treatment-Emergent* Adverse Reactions in Patients Receiving Azilect as Adjunct to Levodopa Therapy in Study 1

	Azilect 1 mg + Levodopa (N=149)	Azilect 0.5 mg + Levodopa (N=164)	Placebo + Levodopa (N=159)
	% of patients	% of patients	% of patients
* Incidence ≥ 2% in Azilect 1 mg group and numerically more frequent than in placebo group
Dyskinesia	18	18	10
Accidental injury	12	8	5
Nausea	12	10	8
Headache	11	8	10
Fall	11	12	8
Weight loss	9	2	3
Constipation	9	4	5
Postural hypotension	9	6	3
Arthralgia	8	6	4
Vomiting	7	4	1
Dry mouth	6	2	3
Rash	6	3	3
Somnolence	6	4	4
Abdominal pain	5	2	1
Anorexia	5	2	1
Diarrhea	5	7	4
Ecchymosis	5	2	3
Dyspepsia	5	4	4
Paresthesia	5	2	3
Abnormal dreams	4	1	1
Hallucinations	4	5	3
Ataxia	3	6	1
Dyspnea	3	5	2
Infection	3	2	2
Neck pain	3	1	1
Sweating	3	2	1
Tenosynovitis	3	1	0
Dystonia	3	2	1
Gingivitis	2	1	1
Hemorrhage	2	1	1
Hernia	2	1	1
Myasthenia	2	2	1

Several of the more common adverse reactions seemed dose-related, including weight loss, postural hypotension, and dry mouth.

Other adverse reactions of potential clinical importance reported in Study 1 by 1% or more of patients treated with rasagiline 1 mg/day as adjunct to levodopa therapy, and at least as frequent as in the placebo group, in descending order of frequency include : skin carcinoma, anemia, albuminuria, amnesia, arthritis, bursitis, cerebrovascular accident, confusion, dysphagia, epistaxis, leg cramps, pruritus, skin ulcer.

There were no significant differences in the safety profile based on age or gender.

Other Adverse Reactions Observed During All Phase 2/3 Clinical Trials

Rasagiline was administered to approximately 1361 patients during all PD phase 2/3 clinical trials. About 283 patients received rasagiline for at least one year, approximately 410 patients received rasagiline for at least two years, 116 patients received rasagiline for at least 3 years, and 245 patients received rasagiline for more than 3 years, with some patients treated for more than 5 years. The long-term safety profile was similar to that observed with shorter duration exposure.

The frequencies listed below represent the proportion of the 1361 individuals exposed to rasagiline who experienced events of the type cited.

All events that occurred at least twice (or once for serious or potentially serious events), except those already listed above, trivial events, terms too vague to be meaningful, adverse events with no plausible relation to treatment, and events that would be expected in patients of the age studied, were reported without regard to determination of a causal relationship to rasagiline.

Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients, infrequent adverse events are defined as those occurring in at least 1/100 to 1/1000 patients and rare adverse events are defined as those occurring in fewer than 1/1000 patients.

Body as a whole: Frequent: asthenia Infrequent: chills, face edema, flank pain, photosensitivity reaction

Cardiovascular system: Frequent: bundle branch block Infrequent: deep thrombophlebitis, heart failure, migraine, myocardial infarct, phlebitis, ventricular tachycardia Rare: arterial thrombosis, atrial arrhythmia, AV block complete, AV block second degree, bigeminy, cerebral hemorrhage, cerebral ischemia, ventricular fibrillation

Digestive system: Frequent: gastrointestinal hemorrhage Infrequent: colitis, esophageal ulcer, esophagitis, fecal incontinence, intestinal obstruction, mouth ulceration, stomach ulcer, stomatitis, tongue edema Rare: hematemesis, hemorrhagic gastritis, intestinal perforation, intestinal stenosis, jaundice, large intestine perforation, megacolon, melena

Hemic and Lymphatic system: Infrequent: macrocytic anemia Rare: purpura, thrombocythemia

Metabolic and Nutritional disorders: Infrequent: hypocalcemia

Musculoskeletal system: Infrequent: bone necrosis, muscle atrophy Rare: arthrosis

Nervous system: Frequent: abnormal gait, anxiety, hyperkinesia, hypertonia, neuropathy, tremor Infrequent: agitation, aphasia, circumoral paresthesia, convulsion, delusions, dementia, dysarthria, dysautonomia, dysesthesia, emotional lability, facial paralysis, foot drop, hemiplegia, hypesthesia, incoordination, manic reaction, myoclonus, neuritis, neurosis, paranoid reaction, personality disorder, psychosis, wrist drop Rare: apathy, delirium, hostility, manic depressive reaction, myelitis, neuralgia, psychotic depression, stupor

Respiratory system: Frequent: cough increased Infrequent: apnea, emphysema, laryngismus, pleural effusion, pneumothorax Rare: interstitial pneumonia, larynx edema, lung fibrosis

Skin and Appendages: Infrequent: eczema, urticaria Rare: exfoliative dermatitis, leukoderma

Special senses: Infrequent: blepharitis, deafness, diplopia, eye hemorrhage, eye pain, glaucoma, keratitis, ptosis, retinal degeneration, taste perversion, visual field defect Rare: blindness, parosmia, photophobia, retinal detachment, retinal hemorrhage, strabismus, taste loss, vestibular disorder

Urogenital system: Frequent: hematuria, urinary incontinence Infrequent: acute kidney failure, dysmenorrhea, dysuria, kidney calculus, nocturia, polyuria, scrotal edema, sexual function abnormal, urinary retention, urination impaired, vaginal hemorrhage, vaginal moniliasis, vaginitis Rare: abnormal ejaculation, amenorrhea, anuria, epididymitis, gynecomastia, hydroureter, leukorrhea, priapism

Post-marketing Experience

The following adverse events not described in sections 4 and 5 have been identified during the post-marketing/post-approval use of Azilect. Because these adverse events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency nor to establish unequivocally a causal relationship to drug exposure: Increased libido including hypersexuality, impulse control symptoms, pathological gambling [see Patient Counseling Information (17.11)]

Drug Interactions

Meperidine

Serious, sometimes fatal reactions have been precipitated with concomitant use of meperidine (e.g., Demerol and other tradenames) and MAO inhibitors including selective MAO-B inhibitors [see Contraindications (4.1)].

Dextromethorphan

The concomitant use of Azilect and dextromethorphan was not allowed in clinical studies. The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior. Therefore, in view of Azilect's MAO inhibitory activity, dextromethorphan should not be used concomitantly with Azilect [see Contraindications (4.2)].

Sympathomimetic Medications

The concomitant use of Azilect and sympathomimetic medications was not allowed in clinical studies. Severe hypertensive reactions have followed the administration of sympathomimetics and non-selective MAO inhibitors. One case of hypertensive crisis has been reported in a patient taking the recommended dose of a selective MAO-B inhibitor and a sympathomimetic medication (ephedrine). Elevated blood pressure was reported in another patient taking the recommended dose of Azilect and ophthalmic drops with a sympathomimetic medication (tetrahydrozoline).

Because Azilect is a selective MAOI, hypertensive reactions are not ordinarily expected with the concomitant use of sympathomimetic medications. Nevertheless, caution should be exercised when concomitantly using recommended doses of Azilect with any sympathomimetic medications including nasal, oral, and ophthalmic decongestants and cold remedies.

MAO Inhibitors

Azilect should not be administered along with other MAO inhibitors because of the increased risk of non-selective MAO inhibition that may lead to a hypertensive crisis [see Contraindications (4.3)].

Antidepressants

Concomitant use of Azilect with one of many classes of antidepressants (e.g., SSRIs, SNRIs, triazolopyridine, tricyclic or tetracyclic antidepressants) is not recommended [see Warnings and Precautions (5.1)].

Levodopa/Carbidopa

[see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

Ciprofloxacin and Other CYP1A2 Inhibitors

Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant ciprofloxacin and other CYP1A2 inhibitors. This could result in increased adverse events [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

Theophylline

[see Clinical Pharmacology (12.3)].

Tyramine/Rasagiline Interaction

MAO in the gastrointestinal tract and liver (primarily type A) is thought to provide vital protection from exogenous amines (e.g., tyramine) that have the capacity, if absorbed intact, to cause a "hypertensive crisis," the so-called "cheese reaction". If large amounts of certain exogenous amines (e.g., from fermented cheese, herring, over-the-counter cough/cold medications) gain access to the systemic circulation because MAO-A has been inhibited, they cause release of norepinephrine which may result in a rise in systemic blood pressure. MAOIs that selectively inhibit MAO-B are largely devoid of the potential to cause tyramine-induced hypertensive crisis.

Results of a special tyramine challenge study indicate that rasagiline is selective for MAO-B at recommended doses and can ordinarily be used without dietary tyramine restriction. However, certain foods (e.g., aged cheeses, such as Stilton cheese) may contain very high amounts (i.e., > 150 mg) of tyramine and could potentially cause a hypertensive cheese reaction in patients taking Azilect due to mild increased sensitivity to tyramine. Patients should be advised to avoid foods (e.g., aged cheese) containing a very large amount of tyramine while taking recommended doses of Azilect because of the potential for large increases in blood pressure. Selectivity for inhibiting MAO-B diminishes in a dose-related manner as the dose is progressively increased above the recommended daily doses.

There were no cases of hypertensive crisis in the clinical development program associated with 1 mg daily rasagiline treatment, in which most patients did not follow dietary tyramine restriction.

Despite the selective inhibition of MAO-B at recommended doses of Azilect, there have been post-marketing reports of patients who experienced significantly elevated blood pressure (including rare cases of hypertensive crisis) after ingestion of unknown amounts of tyramine-rich foods while taking recommended doses of Azilect [see Dosing and Administration (2), and Warnings and Precautions (5.4)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Category C

No effect on embryo-fetal development was observed in a combined mating/fertility and embryo-fetal development study in female rats at doses up to 3 mg/kg/day (approximately 30 times the expected plasma rasagiline exposure (AUC) at the maximum recommended human dose [MRHD, 1 mg/day]). Effects on embryo-fetal development in rabbit have not been adequately assessed.

In a study in which pregnant rats were dosed with rasagiline (0.1, 0.3, 1 mg/kg/day) orally, from the beginning of organogenesis to day 20 post-partum, offspring survival was decreased and offspring body weight was reduced at doses of 0.3 mg/kg/day and 1 mg/kg/day (10 and 16 times the expected plasma rasagiline exposure [AUC] at the MRHD). No plasma data were available at the no-effect dose (0.1 mg/kg); however, that dose is 1 times the MRHD on a mg/m2 basis. Rasagiline's effect on physical and behavioral development was not adequately assessed in this study.

Rasagiline may be given as an adjunct therapy to levodopa/carbidopa treatment. In a study in which pregnant rats were dosed with rasagiline (0.1, 0.3, 1 mg/kg/day) and levodopa/carbidopa (80/20 mg/kg/day) (alone and in combination) throughout the period of organogenesis, there was an increased incidence of wavy ribs in fetuses from rats treated with rasagiline in combination with levodopa/carbidopa at 1/80/20 mg/kg/day (approximately 8 times the plasma AUC expected in humans at the MRHD and 1/1 times the MRHD of levodopa/carbidopa [800/200 mg/day] on a mg/m2 basis). In a study in which pregnant rabbits were dosed throughout the period of organogenesis with rasagiline alone (3 mg/kg) or in combination with levodopa/carbidopa (rasagiline: 0.1, 0.6, 1.2 mg/kg, levodopa/carbidopa: 80/20 mg/kg/day), an increase in embryo-fetal death was noted at rasagiline doses of 0.6 and 1.2 mg/kg/day when administered in combination with levodopa/carbidopa (approximately 7 and 13 times, respectively, the plasma rasagiline AUC at the MRHD). There was an increase in cardiovascular abnormalities with levodopa/carbidopa alone (1/1 times the MRHD on a mg/m2 basis) and to a greater extent when rasagiline (at all doses; 1-13 times the plasma rasagiline AUC at the MRHD) was administered in combination with levodopa/carbidopa.

There are no adequate and well-controlled studies of rasagiline in pregnant women. Therefore, Azilect should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

In rats rasagiline was shown to inhibit prolactin secretion and it may inhibit milk secretion in females.

It is not known whether rasagiline is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Azilect is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of Azilect in the pediatric population have not been studied.

Geriatric Use

Approximately half of patients in clinical trials were 65 years and over. There were no significant differences in the safety profile of the geriatric and non-geriatric patients.

Hepatic Impairment

Rasagiline plasma concentration may be increased in patients with mild (up to 2 fold, Child-Pugh score 5-6), moderate (up to 7 fold, Child-Pugh score 7-9), and severe (Child-Pugh score 10-15) hepatic impairment. Patients with mild hepatic impairment should be given the dose of 0.5 mg/day. Azilect should not be used in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3), Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

Renal Impairment

Dose adjustment of Azilect is not required for patients with mild or moderate renal impairment because Azilect plasma concentrations are not increased in patients with moderate renal impairment. Rasagiline has not been studied in patients with severe renal impairment.

Drug Abuse and Dependence

Controlled Substance

Azilect is not a controlled substance.

Abuse