Ketalar Injection

1. Name Of The Medicinal Product

Ketalar^TM 10 mg/ml, 50 mg/ml, 100 mg/ml Injection.

2. Qualitative And Quantitative Composition

Each 1 ml of solution contains:

Ketalar 10mg/ml Injection : ketamine hydrochloride Ph Eur equivalent to 10 mg ketamine base per ml.

Ketalar 50mg/ml Injection : ketamine hydrochloride Ph Eur equivalent to 50 mg ketamine base per ml.

Ketalar 100mg/ml Injection: ketamine hydrochloride Ph Eur equivalent to 100 mg ketamine base per ml.

3. Pharmaceutical Form

Solution for injection or infusion.

A clear solution for injection or infusion.

4. Clinical Particulars

4.1 Therapeutic Indications

Ketalar is recommended:

As an anaesthetic agent for diagnostic and surgical procedures. When used by intravenous or intramuscular injection, Ketalar is best suited for short procedures. With additional doses, or by intravenous infusion, Ketalar can be used for longer procedures. If skeletal muscle relaxation is desired, a muscle relaxant should be used and respiration should be supported.

For the induction of anaesthesia prior to the administration of other general anaesthetic agents.

To supplement other anaesthetic agents.

Specific areas of application or types of procedures:-

When the intramuscular route of administration is preferred.

Debridement, painful dressings, and skin grafting in burned patients, as well as other superficial surgical procedures.

Neurodiagnostic procedures such as pneumoencephalograms, ventriculograms, myelograms, and lumbar punctures.

Diagnostic and operative procedures of the eye, ear, nose, and mouth, including dental extractions.

Note: Eye movements may persist during ophthalmological procedures.

Anaesthesia in poor-risk patients with depression of vital functions or where depression of vital functions must be avoided, if at all possible.

Orthopaedic procedures such as closed reductions, manipulations, femoral pinning, amputations, and biopsies.

Sigmoidoscopy and minor surgery of the anus and rectum, circumcision and pilonidal sinus.

Cardiac catheterization procedures.

Caesarian section; as an induction agent in the absence of elevated blood pressure.

Anaesthesia in the asthmatic patient, either to minimise the risks of an attack of bronchospasm developing, or in the presence of bronchospasm where anaesthesia cannot be delayed.

4.2 Posology And Method Of Administration

For intravenous infusion, intravenous injection or intramuscular injection.

NOTE: All doses are given in terms of ketamine base

Adults, elderly (over 65 years) and children:

For surgery in elderly patients ketamine has been shown to be suitable either alone or supplemented with other anaesthetic agents.

Preoperative preparations

Ketalar has been safely used alone when the stomach was not empty. However, since the need for supplemental agents and muscle relaxants cannot be predicted, when preparing for elective surgery it is advisable that nothing be given by mouth for at least six hours prior to anaesthesia.

Premedication with an anticholinergic agent (e.g. atropine, hyoscine or glycopyrolate) or another drying agent should be given at an appropriate interval prior to induction to reduce ketamine-induced hypersalivation..

Midazolam, diazepam, lorazepam, or flunitrazepam used as a premedicant or as an adjunct to ketamine, have been effective in reducing the incidence of emergence reactions.

Onset and duration

As with other general anaesthetic agents, the individual response to Ketalar is somewhat varied depending on the dose, route of administration, age of patient, and concomitant use of other agents, so that dosage recommendation cannot be absolutely fixed. The dose should be titrated against the patient's requirements.

Because of rapid induction following intravenous injection, the patient should be in a supported position during administration. An intravenous dose of 2 mg/kg of bodyweight usually produces surgical anaesthesia within 30 seconds after injection and the anaesthetic effect usually lasts 5 to 10 minutes. An intramuscular dose of 10 mg/kg of bodyweight usually produces surgical anaesthesia within 3 to 4 minutes following injection and the anaesthetic effect usually lasts 12 to 25 minutes. Return to consciousness is gradual.

A. Ketalar as the sole anaesthetic agent

Intravenous Infusion

The use of Ketalar by continuous infusion enables the dose to be titrated more closely, thereby reducing the amount of drug administered compared with intermittent administration. This results in a shorter recovery time and better stability of vital signs.

A solution containing 1 mg/ml of ketamine in dextrose 5% or sodium chloride 0.9% is suitable for administration by infusion.

General Anesthesia Induction

An infusion corresponding to 0.5 – 2 mg/kg as total induction dose.

Maintenance of anaesthesia

Anaesthesia may be maintained using a microdrip infusion of 10 - 45 microgram/kg/min (approximately 1 – 3 mg/min).

The rate of infusion will depend on the patient's reaction and response to anaesthesia. The dosage required may be reduced when a long acting neuromuscular blocking agent is used.

Intermittent Injection

Induction

Intravenous Route

The initial dose of Ketalar administered intravenously may range from 1 mg/kg to 4.5mg/kg (in terms of ketamine base).The average amount required to produce 5 to 10 minutes of surgical anaesthesia has been 2.0 mg/kg. It is recommended that intravenous administration be accomplished slowly (over a period of 60 seconds). More rapid administration may result in respiratory depression and enhanced pressor response.

Note: the 100 mg/ml concentration of ketamine should not be injected intravenously without proper dilution. It is recommended that the drug be diluted with an equal volume of either sterile water for injection, normal saline, or 5% dextrose in water.

Intramuscular Route

The initial dose of Ketalar administered intramuscularly may range from 6.5 mg/kg to 13 mg/kg (in terms of ketamine base). A low initial intramuscular dose of 4 mg/kg has been used in diagnostic manoeuvres and procedures not involving intensely painful stimuli. A dose of 10 mg/kg will usually produce 12 to 25 minutes of surgical anaesthesia.

Dosage in Hepatic Insufficiency:

Dose reductions should be considered in patients with cirrhosis or other types of liver impairment. (see section 4.4 Special Warnings and Special Precautions for Use).

Maintenance of general anaesthesia

Lightening of anaesthesia may be indicated by nystagmus, movements in response to stimulation, and vocalization. Anaesthesia is maintained by the administration of additional doses of Ketalar by either the intravenous or intramuscular route.

Each additional dose is from ½ to the full induction dose recommended above for the route selected for maintenance, regardless of the route used for induction.

The larger the total amount of Ketalar administered, the longer will be the time to complete recovery.

Purposeless and tonic-clonic movements of extremities may occur during the course of anaesthesia. These movements do not imply a light plane and are not indicative of the need for additional doses of the anaesthetic.

B. Ketalar as induction agent prior to the use of other general anaesthetics

Induction is accomplished by a full intravenous or intramuscular dose of Ketalar as defined above. If Ketalar has been administered intravenously and the principal anaesthetic is slow-acting, a second dose of Ketalar may be required 5 to 8 minutes following the initial dose. If Ketalar has been administered intramuscularly and the principal anaesthetic is rapid-acting, administration of the principal anaesthetic may be delayed up to 15 minutes following the injection of Ketalar.

C. Ketalar as supplement to anaesthetic agents

Ketalar is clinically compatible with the commonly used general and local anaesthetic agents when an adequate respiratory exchange is maintained. The dose of Ketalar for use in conjunction with other anaesthetic agents is usually in the same range as the dosage stated above; however, the use of another anaesthetic agent may allow a reduction in the dose of Ketalar.

D. Management of patients in recovery

Following the procedure the patient should be observed but left undisturbed. This does not preclude the monitoring of vital signs. If, during the recovery, the patient shows any indication of emergence delirium, consideration may be given to the use of diazepam (5 to 10 mg I.V. in an adult). A hypnotic dose of a thiobarbiturate (50 to 100 mg I.V.) may be used to terminate severe emergence reactions. If any one of these agents is employed, the patient may experience a longer recovery period.

4.3 Contraindications

Ketalar is contra-indicated in persons in whom an elevation of blood pressure would constitute a serious hazard (see section 4.8 Undesirable effects). Ketamine hydrochloride is contraindicated in patients who have shown hypersensitivity to the drug or its components. Ketalar should not be used in patients with eclampsia or pre-eclampsia, severe coronary or myocardial disease, cerebrovascular accident or cerebral trauma.

4.4 Special Warnings And Precautions For Use

To be used only in hospitals by or under the supervision of experienced medically qualified anaesthetists except under emergency conditions.

As with any general anaesthetic agent, resuscitative equipment should be available and ready for use.

Respiratory depression may occur with overdosage of Ketalar, in which case supportive ventilation should be employed. Mechanical support of respiration is preferred to the administration of analeptics.

The intravenous dose should be administered over a period of 60 seconds. More rapid administration may result in transient respiratory depression or apnoea and enhanced pressor response.

Because pharyngeal and laryngeal reflexes usually remain active, mechanical stimulation of the pharynx should be avoided unless muscle relaxants, with proper attention to respiration, are used.

Although aspiration of contrast medium has been reported during Ketalar anaesthesia under experimental conditions (Taylor, P A and Towey, R M, Brit. Med. J. 1971, 2: 688), in clinical practice aspiration is seldom a problem.

In surgical procedures involving visceral pain pathways, Ketalar should be supplemented with an agent which obtunds visceral pain.

When Ketalar is used on an outpatient basis, the patient should not be released until recovery from anaesthesia is complete and then should be accompanied by a responsible adult.

Ketalar should be used with caution in patients with the following conditions:

Use with caution in the chronic alcoholic and the acutely alcohol-intoxicated patient.

Ketamine is metabolised in the liver and hepatic clearance is required for termination of clinical effects. A prolonged duration of action may occur in patients with cirrhosis or other types of liver impairment. Dose reductions should be considered in these patients.

Since an increase in cerebrospinal fluid (CSF) pressure has been reported during Ketalar anaesthesia, Ketalar should be used with special caution in patients with preanaesthetic elevated cerebrospinal fluid pressure.

Use with caution in patients with globe injuries and increased intraocular pressure (e.g. glaucoma) because the pressure may increase significantly after a single dose of ketamine.

Use with caution in patients with neurotic traits or psychiatric illness (e.g. schizophrenia and acute psychosis)

Use in caution in patients with acute intermittent porphyria.

Use in caution in patients with seizures.

Use in caution in patients with hyperthyroidism or patients receiving thyroid replacement (increased risk of hypertension and tachycardia)

Use in caution in patients with pulmonary or upper respiratory infection (ketamine sensitises the gag reflex, potentially causing laryngospasm)

Use in caution in patients with intracranial mass lesions, a presence of head injury, or hydrocephalus.

Emergence Reaction

The psychological manifestations vary in severity between pleasant dream-like states, vivid imagery, hallucinations, nightmares or illusions and emergence delirium (often consisting of dissociative or floating sensations), In some cases these states have been accompanied by confusion, excitement, and irrational behaviour which a few pateients recall as an unpleasant experience. (See section 4.8 Undesirable Effects).

Emergence delirium phenomena may occur during the recovery period. The incidence of these reactions may be reduced if verbal and tactile stimulation of the patient is minimised during the recovery period. This does not preclude the monitoring of vital signs.

Because of the substantial increase in myocardial oxygen consumption, ketamine should be used in caution in patients with hypovolemia, dehydration or cardiac disease, especially coronary artery disease (e.g. congestive heart failure, myocardial ischemia and myocardial infarction). In addition ketamine should be used with caution in patients with mild-to-moderate hypertension and tachyarrythmais.

Cardiac function should be continually monitored during the procedure in patients found to have hypertension or cardiac decompensation.

Ketalar has been reported as being a drug of abuse. If used on a daily basis for a few weeks, dependence and tolerance may develop, particularly in individuals with a history of drug abuse and dependence. Therefore the use of Ketalar should be closely supervised and it should be prescribed and administered with caution.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Prolonged recovery time may occur if barbiturates and/or narcotics are used concurrently with Ketalar.

Ketalar is chemically incompatible with barbiturates and diazepam because of precipitate formation. Therefore, these should not be mixed in the same syringe or infusion fluid.

Ketamine may potentiate the neuromuscular blocking effects of atracurium and tubocurarine including respiratory depression with apnea.

The use of halogenated anesthetics concomitantly with ketamine can lengthen the elimination half-life of ketamine and delay recovery from anesthesia. Concurrent use of ketamine (especially in high doses or when rapidly administered) with halogenated anesthetics can increase the risk of developing bradycardia, hypotension or decreased cardiac output.

The use of ketamine with other central nervous system (CNS) depressants (e.g. ethanol, phenothiazines, sedating H₁ – blockers or skeletal muscle relaxants) can potentiate CNS depression and/or increase risk of developing respiratory depression. Reduced doses of ketamine may be required with concurrent administration of other anxiolytics, sedatives and hypnotics.

Ketamine has been reported to antagonise the hypnotic effect of thiopental.

Patients taking thyroid hormones have an increased risk of developing hypertension and tachycardia when given ketamine.

Concomitant use of antihypertensive agents and ketamine increases the risk of developing hypotension.

When ketamine and theophylline are given concurrently, a clinically significant reduction in the seizure threshold is observed. Unpredictable extensor-type seizures have been reported with concurrent administration of these agents.

4.6 Pregnancy And Lactation

Ketalar crosses the placenta. This should be borne in mind during operative obstetric procedures in pregnancy. With the exception of administration during surgery for abdominal delivery or vaginal delivery, no controlled clinical studies in pregnancy have been conducted. The safe use in pregnancy, and in lactation, has not been established and such use is not recommended.

4.7 Effects On Ability To Drive And Use Machines

Patients should be cautioned that driving a car, operating hazardous machinery or engaging in hazardous activities should not be undertaken for 24 hours or more after anaesthesia.

4.8 Undesirable Effects

Cardiac and Vascular Disorders:

Temporary elevation of blood pressure and pulse rate is frequently observed following administration of ketamine hydrochloride. However, hypotension and bradycardia have been reported. Arrhythmias have also occurred. The median peak rise of blood pressure has ranged from 20 to 25 per cent of preanaesthetic values. Depending on the condition of the patient, this elevation of blood pressure may be considered an adverse reaction or a beneficial effect.

Respiratory, Thoracic and Mediastinal Disorders:

Depression of respiration or apnoea may occur following over rapid intravenous administration or high doses of ketamine hydrochloride. Laryngospasm and other forms of airway obstruction have occurred during ketamine hydrochloride anaesthesia. Increased salivation leading to respiratory difficulties may occur unless an antisialogogue is used.

Eye Disorders:

Diplopia and nystagmus may occur following ketamine hydrochloride administration. A elevation in intraocular pressure may also occur.

Psychiatric Disorders:

Reports suggest that ketamine produces a variety of symptoms including, but not limited to, flashbacks, hallucinations, nightmares, illusions, dysphoria, anxiety, insomnia or disorientation (often consisting of dissociative or floating sensations)..

During recovery from anaesthesia the patient may experience emergence delirium, characterised by vivid dreams (pleasant or unpleasant), with or without psychomotor activity, manifested by confusion and irrational behaviour. The fact that these reactions are observed less often in the young (15 years of age or less) makes Ketalar especially useful in paediatric anaesthesia. These reactions are also less frequent in the elderly (over 65 years of age) patient. The incidence of emergence reactions is reduced as experience with the drug is gained. No residual psychological effects are known to have resulted from the use of Ketalar.

Nervous System Disorders:

In some patients, enhanced skeletal muscle tone may be manifested by tonic and clonic movements sometimes resembling seizures. These movements do not imply a light plane of anaesthesia and are not indicative of a need for additional doses of the anaesthetic.

Metabolism and Nutritional Disorders:

Anorexia has been observed, however this is not usually severe and allows the great majority of patients to take liquids by mouth shortly after regaining conciousness.

Gastro-intestinal Disorders:

Nausea, and vomiting have been observed; however, these are uncommon and are not usually severe. The great majority of patients are able to take liquids by mouth shortly after regaining consciousness. Hypersalivation (See section 4.2 Posology and Method of Administration – Preoperative Preparations).

Immune System Disorders:

There have been a number of reported cases of anaphylaxis.

General Disorders and Administration Site Conditions:

Local pain and exanthema at the injection site have infrequently been reported.

Skin and Subcutaneous Tissue Disorders:

Transient erythema and/or morbilliform rash have also been reported.

4.9 Overdose

Respiratory depression can result from an overdosage of ketamine hydrochloride. Supportive ventilation should be employed. Mechanical support of respiration that will maintain adequate blood oxygen saturation and carbon dioxide elimination is preferred to administration of analeptics.

Ketalar has a wide margin of safety; several instances of unintentional administration of overdoses of Ketalar (up to 10 times that usually required) have been followed by prolonged but complete recovery.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Ketamine is a rapidly acting general anaesthetic for intravenous or intramuscular use with a distinct pharmacological action. Ketamine hydrochloride produces dissociative anaesthesia characterised by catalepsy, amnesia, and marked analgesia which may persist into the recovery period. Pharyngeal-laryngeal reflexes remain normal and skeletal muscle tone may be normal or can be enhanced to varying degrees. Mild cardiac and respiratory stimulation and occasionally respiratory depression occur.

Mechanism of Action:

Ketamine induces sedation, immobility, amnesia and marked analgesia. The anesthetic state produced by ketamine has been termed “dissociative anesthesia” in that it appears to selectively interrupt association pathways of the brain before producing somesthetic sensory blockade. It may selectively depress the thalamoneocortical system before significantly obtunding the more ancient cerebral centers and pathways (reticular-activating and limbic systems). Numerous theories have been proposed to explain the effects of ketamine, including binding to N-methyl-D-aspartate (NMDA) receptors in the CNS, interactions with opiate receptors at central and spinal sites and interaction with norepinephrine, serotonin and muscarinic cholinergic receptors. The activity on NMDA receptors may be responsible for the analgesic as well as psychiatric (psychosis) effects of ketamine. Ketamine has sympathomimetic activity resulting in tachycardia, hypertension, increased myocardial and cerebral oxygen consumption, increased cerebral blood flow and increased intracranial and intraocular pressure. Ketamine is also a potent bronchodilator. Clinical effects observed following ketamine administration include increased blood pressure, increased muscle tone (may resemble catatonia), opening of eyes (usually accompanied by nystagmus) and increased myocardial oxygen consumption.

5.2 Pharmacokinetic Properties

Ketamine is rapidly distributed into perfused tissues including brain and placenta. Animal studies have shown ketamine to be highly concentrated in body fat, liver and lung. Biotransformation takes place in liver. Termination of anaesthetic is partly by redistribution from brain to other tissues and partly by metabolism. Elimination half-life is approximately 2-3 hours, and excretion renal, mostly as conjugated metabolites.

5.3 Preclinical Safety Data

Preclinical safety data does not add anything of further significance to the prescriber.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Ketalar 10mg/ml Injection: sodium chloride, benzethonium chloride, water for injection

Ketalar 50mg/ml Injection: benzethonium chloride, water for injection

Ketalar 100mg/ml Injection: benzethonium chloride, water for injection

6.2 Incompatibilities

Ketalar is chemically incompatible with barbiturates and diazepam because of precipitate formation. Therefore, these should not be mixed in the same syringe or infusion fluid.

6.3 Shelf Life

Ketelar 10mg/ml and 50mg/ml: 60 months

Ketelar 100mg/ml: 36 months

For single use only. Discard any unused product at the end of each operating session.

After dilution the solutions should be used immediately.

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions. Do not freeze. Store in the original container. Discard any unused product at the end of each operating session.

6.5 Nature And Contents Of Container

Ketalar 10mg/ml Injection: 20 ml white neutral glass vial with rubber closure and aluminium flip-off cap containing 10 mg ketamine base per ml.

Ketalar 50mg/ml Injection: 12 ml vials containing 10 ml of solution as 50 mg ketamine base per ml.

Ketalar 100mg/ml Injection: 12 ml vials containing 10 ml of solution as 100 mg ketamine base per ml.

6.6 Special Precautions For Disposal And Other Handling

For single use only. Discard any unused product at the end of each operating session.

See Section 4.2 Posology and method of administration.

7. Marketing Authorisation Holder

Pfizer Limited, Sandwich, Kent CT13 9NJ, United Kingdom

8. Marketing Authorisation Number(S)

PL 00057/0529, PL 00057/0530, PL 00057/0531

9. Date Of First Authorisation/Renewal Of The Authorisation

1^st July 2003

10. Date Of Revision Of The Text

December 2009

Company Reference: KE 7_0 UK

Genelan NF Liquid

Pronunciation: klor-fen-EER-a-meen/ dex -troe-meth-OR-fan/gwye-FEN-e-sin/ fen-ill-EF-rin
Generic Name: Chlorpheniramine/Dextromethorphan/Guaifenesin/Phenylephrine
Brand Name: Examples include Genelan NF and Zotex-DM

Genelan NF Liquid is used for:

Relieving symptoms of sinus congestion, runny nose, sneezing, cough, and throat and airway irritation due to colds, upper respiratory infections, and allergies. It may also be used for other conditions as determined by your doctor.

Genelan NF Liquid is an antihistamine, decongestant, cough suppressant, and expectorant combination. It works by constricting blood vessels and reducing swelling in the nasal passages, loosening mucus and lung secretions in the chest, and making coughs more productive. The antihistamine works by blocking the action of histamine, which helps reduce symptoms such as watery eyes and sneezing while the cough suppressant works in the brain to help decrease the cough reflex to reduce a dry cough.

Do NOT use Genelan NF Liquid if:

• you are allergic to any ingredient in Genelan NF Liquid


• you have severe high blood pressure, severe heart blood vessel disease, rapid heartbeat, or severe heart problems


• you are unable to urinate or are having an asthma attack


• you take sodium oxybate (GHB) or if you have taken furazolidone or a monoamine oxidase (MAO) inhibitor (eg, phenelzine) within the last 14 days

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

Before using Genelan NF Liquid:

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

• if you are pregnant, plan 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 fast, slow, or irregular heartbeat


• if you have a history of adrenal gland problems (eg, adrenal gland tumor), heart problems, high blood pressure, diabetes, heart blood vessel problems, stroke, glaucoma, a blockage of your bladder, stomach, or intestines, ulcers, trouble urinating, an enlarged prostate, seizures, or an overactive thyroid


• if you have a history of asthma, chronic cough, lung problems (eg, chronic bronchitis, emphysema), or chronic obstructive pulmonary disease (COPD), or if cough occurs with large amounts of mucus

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

• Beta-blockers (eg, propranolol), COMT inhibitors (eg, tolcapone), furazolidone, indomethacin, MAO inhibitors (eg, phenelzine), sodium oxybate (GHB), or tricyclic antidepressants (eg, amitriptyline) because side effects of Genelan NF Liquid may be increased


• Digoxin or droxidopa because risk of irregular heartbeat or heart attack may be increased


• Bromocriptine or hydantoins (eg, phenytoin) because side effects may be increased by Genelan NF Liquid


• Guanadrel, guanethidine, mecamylamine, methyldopa, or reserpine because effectiveness may be decreased by Genelan NF Liquid

This may not be a complete list of all interactions that may occur. Ask your health care provider if Genelan NF Liquid 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 Genelan NF Liquid:

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

• Genelan NF Liquid may be taken with or without food.


• Use a measuring device marked for medicine dosing. Ask your pharmacist for help if you are unsure of how to measure your dose.


• If you miss a dose of Genelan NF Liquid, 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 Genelan NF Liquid.

Important safety information:

• Genelan NF Liquid may cause dizziness, drowsiness, or blurred vision. Do not drive, operate machinery, or do anything else that could be dangerous until you know how you react to Genelan NF Liquid. Using Genelan NF Liquid alone, with certain other medicines, or with alcohol may lessen your ability to drive or perform other potentially dangerous tasks.


• Do not take diet or appetite control medicines while you are taking Genelan NF Liquid without checking with your doctor.


• Genelan NF Liquid contains phenylephrine. Before you begin taking any new prescription or nonprescription medicine, read the ingredients to see if it also contains phenylephrine. If it does or if you are uncertain, contact your doctor or pharmacist.


• Do NOT exceed the recommended dose or take Genelan NF Liquid for longer than prescribed without checking with your doctor.


• If your symptoms do not improve within 5 to 7 days or if they become worse, check with your doctor.


• Genelan NF Liquid may cause increased sensitivity to the sun. Avoid exposure to the sun, sunlamps, or tanning booths until you know how you react to Genelan NF Liquid. Use a sunscreen or protective clothing if you must be outside for a prolonged period.


• If you are scheduled for allergy skin testing, do not take Genelan NF Liquid for several days before the test because it may decrease your response to the skin tests.


• Before you have any medical or dental treatments, emergency care, or surgery, tell the doctor or dentist that you are using Genelan NF Liquid.


• Use Genelan NF Liquid with caution in the ELDERLY because they may be more sensitive to its effects.


• Caution is advised when using Genelan NF Liquid in CHILDREN because they may be more sensitive to its effects.


• PREGNANCY and BREAST-FEEDING: If you become pregnant while taking Genelan NF Liquid, discuss with your doctor the benefits and risks of using Genelan NF Liquid during pregnancy. It is unknown if Genelan NF Liquid is excreted in breast milk. Do not breast-feed while taking Genelan NF Liquid.

Possible side effects of Genelan NF Liquid:

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; diarrhea; dizziness; drowsiness; excitability; headache; loss of appetite; nausea; nervousness or anxiety; trouble sleeping; upset stomach; vomiting; weakness.

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

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); difficulty urinating or inability to urinate; fast or irregular heartbeat; hallucinations; seizures; severe dizziness, lightheadedness, or headache; tremor; trouble sleeping; vision changes.

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: Genelan NF 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 blurred vision; confusion; hallucinations; seizures; severe dizziness, lightheadedness, or headache; severe drowsiness; unusually fast, slow, or irregular heartbeat; vomiting.

Proper storage of Genelan NF Liquid:

Store Genelan NF Liquid at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Genelan NF Liquid out of the reach of children and away from pets.

General information:

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


• Genelan NF Liquid 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 Genelan NF Liquid. 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 Genelan NF resources

• Genelan NF Side Effects (in more detail)
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• Genelan NF Drug Interactions
• Genelan NF Support Group
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Dosage Form: tablet
Pramipexole DIHYDROCHLORIDE TABLETS

8019

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Pramipexole Description

Pramipexole dihydrochloride tablets contain Pramipexole, a nonergot dopamine agonist. The chemical name of Pramipexole dihydrochloride is (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole dihydrochloride monohydrate.

The structural formula is:

C10H21C12N3OS M.W. 302.25

Pramipexole dihydrochloride is a white to off-white crystalline powder substance. Melting occurs in the range of 296°C to 301°C, with decomposition. Pramipexole dihydrochloride is more than 20% soluble in water, about 8% in methanol, about 0.5% in ethanol, and practically insoluble in dichloromethane.

Pramipexole dihydrochloride tablets, for oral administration, contain 0.75 mg of Pramipexole dihydrochloride monohydrate. Inactive ingredients consist of colloidal silicon dioxide, magnesium stearate, mannitol, microcrystalline cellulose, povidone, sodium starch glycolate, and sodium stearyl fumarate.

Pramipexole - Clinical Pharmacology

Mechanism of Action

Pramipexole is a nonergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors, binding with higher affinity to D3 than to D2 or D4 receptor subtypes.

Parkinson’s Disease

The precise mechanism of action of Pramipexole as a treatment for Parkinson's disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum. This conclusion is supported by electrophysiologic studies in animals that have demonstrated that Pramipexole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum. The relevance of D3 receptor binding in Parkinson’s disease is unknown.

Pharmacokinetics

Pramipexole displays linear pharmacokinetics over the clinical dosage range. Its terminal half-life is about 8 hours in young healthy volunteers and about 12 hours in elderly volunteers (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations). Steady-state concentrations are achieved within 2 days of dosing.

Absorption

Pramipexole is rapidly absorbed, reaching peak concentrations in approximately 2 hours. The absolute bioavailability of Pramipexole is greater than 90%, indicating that it is well absorbed and undergoes little presystemic metabolism. Food does not affect the extent of Pramipexole absorption, although the time of maximum plasma concentration (Tmax) is increased by about 1 hour when the drug is taken with a meal.

Distribution

Pramipexole is extensively distributed, having a volume of distribution of about 500 L (coefficient of variation [CV] = 20%). It is about 15% bound to plasma proteins. Pramipexole distributes into red blood cells as indicated by an erythrocyte-to-plasma ratio of approximately 2.

Metabolism and Elimination

The terminal half-life of Pramipexole is about 8 hours in healthy volunteers and 12 hours in elderly volunteers.

Urinary excretion is the major route of Pramipexole elimination, with 90% of a Pramipexole dose recovered in urine, almost all as unchanged drug. Nonrenal routes may contribute to a small extent to Pramipexole elimination, although no metabolites have been identified in plasma or urine. The renal clearance of Pramipexole is approximately 400 mL/min (CV = 25%), approximately three times higher than the glomerular filtration rate. Thus, Pramipexole is secreted by the renal tubules, probably by the organic cation transport system.

Pharmacokinetics in Special Populations

Because therapy with Pramipexole dihydrochloride tablets is initiated at a low dose and gradually titrated upward according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose based on gender, weight, or age is not necessary. However, renal insufficiency, which can cause a large decrease in the ability to eliminate Pramipexole, may necessitate dosage adjustment (see CLINICAL PHARMACOLOGY, Renal Insufficiency).

Gender

Pramipexole clearance is about 30% lower in women than in men, but most of this difference can be accounted for by differences in body weight. There is no difference in half-life between males and females.

Age

Pramipexole clearance decreases with age as the half-life and clearance are about 40% longer and 30% lower, respectively, in elderly (aged 65 years or older) compared with young healthy volunteers (aged less than 40 years). This difference is most likely due to the well-known reduction in renal function with age, since Pramipexole clearance is correlated with renal function, as measured by creatinine clearance (see CLINICAL PHARMACOLOGY, RenalInsufficiency).

Parkinson's Disease Patients

A cross-study comparison of data suggests that the clearance of Pramipexole may be reduced by about 30% in Parkinson's disease patients compared with healthy elderly volunteers. The reason for this difference appears to be reduced renal function in Parkinson's disease patients, which may be related to their poorer general health. The pharmacokinetics of Pramipexole were comparable between early and advanced Parkinson's disease patients.

Pediatric

The pharmacokinetics of Pramipexole in the pediatric population have not been evaluated.

Hepatic Insufficiency

The influence of hepatic insufficiency on Pramipexole pharmacokinetics has not been evaluated. Because approximately 90% of the recovered dose is excreted in the urine as unchanged drug, hepatic impairment would not be expected to have a significant effect on Pramipexole elimination.

Renal Insufficiency

The clearance of Pramipexole was about 75% lower in patients with severe renal impairment (creatinine clearance approximately 20 mL/min) and about 60% lower in patients with moderate impairment (creatinine clearance approximately 40 mL/min) compared with healthy volunteers. Also, it took longer to achieve steady state. A lower starting and/or maintenance dose may be appropriate in these patients (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). In patients with varying degrees of renal impairment, Pramipexole clearance correlates well with creatinine clearance. Therefore, creatinine clearance can be used as a predictor of the extent of decrease in Pramipexole clearance. Pramipexole clearance is extremely low in dialysis patients, as a negligible amount of Pramipexole is removed by dialysis. Caution should be exercised when administering Pramipexole to patients with renal disease.

CLINICAL STUDIES

Parkinson's Disease

The effectiveness of Pramipexole dihydrochloride tablets in the treatment of Parkinson's disease was evaluated in a multinational drug development program consisting of seven randomized, controlled trials. Three were conducted in patients with early Parkinson's disease who were not receiving concomitant levodopa, and four were conducted in patients with advanced Parkinson's disease who were receiving concomitant levodopa. Among these seven studies, three studies provide the most persuasive evidence of Pramipexole's effectiveness in the management of patients with Parkinson's disease who were and were not receiving concomitant levodopa. Two of these three trials enrolled patients with early Parkinson's disease (not receiving levodopa), and one enrolled patients with advanced Parkinson's disease who were receiving maximally tolerated doses of levodopa.

In all studies, the Unified Parkinson's Disease Rating Scale (UPDRS), or one or more of its subparts, served as the primary outcome assessment measure. The UPDRS is a four-part multi-item rating scale intended to evaluate mentation (part I), Activities of Daily Living (ADL) (part II), motor performance (part III), and complications of therapy (part IV).

Part II of the UPDRS contains 13 questions relating to ADL, which are scored from 0 (normal) to 4 (maximal severity) for a maximum (worst) score of 52. Part III of the UPDRS contains 27 questions (for 14 items) and is scored as described for part II. It is designed to assess the severity of the cardinal motor findings in patients with Parkinson's disease (e.g., tremor, rigidity, bradykinesia, postural instability, etc.), scored for different body regions, and has a maximum (worst) score of 108.

Studies in Patients With Early Parkinson's Disease

Patients (N = 599) in the two studies of early Parkinson's disease had a mean disease duration of 2 years, limited or no prior exposure to levodopa (generally none in the preceding 6 months), and were not experiencing the "on-off" phenomenon and dyskinesia characteristic of later stages of the disease.

One of the two early Parkinson's disease studies (N = 335) was a double-blind, placebo-controlled, parallel trial consisting of a 7 week dose-escalation period and a 6 month maintenance period. Patients could be on selegiline, anticholinergics, or both, but could not be on levodopa products or amantadine. Patients were randomized to Pramipexole dihydrochloride tablets or placebo. Patients treated with Pramipexole dihydrochloride tablets had a starting daily dose of 0.375 mg and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses. At the end of the 6 month maintenance period, the mean improvement from baseline on the UPDRS part II (ADL) total score was 1.9 in the group receiving Pramipexole dihydrochloride tablets and -0.4 in the placebo group, a difference that was statistically significant. The mean improvement from baseline on the UPDRS part III total score was 5.0 in the group receiving Pramipexole dihydrochloride tablets and -0.8 in the placebo group, a difference that was also statistically significant. A statistically significant difference between groups in favor of Pramipexole dihydrochloride tablets was seen beginning at week 2 of the UPDRS part II (maximum dose 0.75 mg/day) and at week 3 of the UPDRS part III (maximum dose 1.5 mg/day).

The second early Parkinson's disease study (N = 264) was a double-blind, placebo-controlled, parallel trial consisting of a 6 week dose-escalation period and a 4 week maintenance period. Patients could be on selegiline, anticholinergics, amantadine, or any combination of these, but could not be on levodopa products. Patients were randomized to 1 of 4 fixed doses of Pramipexole dihydrochloride tablets (1.5 mg, 3 mg, 4.5 mg, or 6 mg per day) or placebo. At the end of the 4 week maintenance period, the mean improvement from baseline on the UPDRS part II total score was 1.8 in the patients treated with Pramipexole dihydrochloride tablets, regardless of assigned dose group, and 0.3 in placebo-treated patients. The mean improvement from baseline on the UPDRS part III total score was 4.2 in patients treated with Pramipexole dihydrochloride tablets and 0.6 in placebo-treated patients. No dose-response relationship was demonstrated. The between-treatment differences on both parts of the UPDRS were statistically significant in favor of Pramipexole dihydrochloride tablets for all doses.

No differences in effectiveness based on age or gender were detected. There were too few non-Caucasian patients to evaluate the effect of race. Patients receiving selegiline or anticholinergics had responses similar to patients not receiving these drugs.

Studies in Patients With Advanced Parkinson's Disease

In the advanced Parkinson's disease study, the primary assessments were the UPDRS and daily diaries that quantified amounts of "on" and "off" time.

Patients in the advanced Parkinson's disease study (N = 360) had a mean disease duration of 9 years, had been exposed to levodopa for long periods of time (mean 8 years), used concomitant levodopa during the trial, and had "on-off" periods.

The advanced Parkinson's disease study was a double-blind, placebo-controlled, parallel trial consisting of a 7 week dose-escalation period and a 6 month maintenance period. Patients were all treated with concomitant levodopa products and could additionally be on concomitant selegiline, anticholinergics, amantadine, or any combination. Patients treated with Pramipexole dihydrochloride tablets had a starting dose of 0.375 mg/day and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses. At selected times during the 6 month maintenance period, patients were asked to record the amount of "off," "on," or "on with dyskinesia" time per day for several sequential days. At the end of the 6 month maintenance period, the mean improvement from baseline on the UPDRS part II total score was 2.7 in the group treated with Pramipexole dihydrochloride tablets and 0.5 in the placebo group, a difference that was statistically significant. The mean improvement from baseline on the UPDRS part III total score was 5.6 in the group treated with Pramipexole dihydrochloride tablets and 2.8 in the placebo group, a difference that was statistically significant. A statistically significant difference between groups in favor of Pramipexole dihydrochloride tablets was seen at week 3 of the UPDRS part II (maximum dose 1.5 mg/day) and at week 2 of the UPDRS part III (maximum dose 0.75 mg/day). Dosage reduction of levodopa was allowed during this study if dyskinesia (or hallucinations) developed; levodopa dosage reduction occurred in 76% of patients treated with Pramipexole dihydrochloride tablets versus 54% of placebo patients. On average, the levodopa dose was reduced 27%.

The mean number of "off" hours per day during baseline was 6 hours for both treatment groups. Throughout the trial, patients treated with Pramipexole dihydrochloride tablets had a mean of 4 "off" hours per day, while placebo-treated patients continued to experience 6 "off" hours per day.

No differences in effectiveness based on age or gender were detected. There were too few non-Caucasian patients to evaluate the effect of race.

Indications and Usage for Pramipexole

Parkinson's Disease

Pramipexole dihydrochloride tablets are indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease.

The effectiveness of Pramipexole dihydrochloride tablets was demonstrated in randomized, controlled trials in patients with early Parkinson's disease who were not receiving concomitant levodopa therapy as well as in patients with advanced disease on concomitant levodopa (see CLINICAL STUDIES).

Contraindications

Pramipexole dihydrochloride tablets are contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.

Warnings

Falling Asleep During Activities of Daily Living

Patients treated with Pramipexole dihydrochloride tablets have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles which sometimes resulted in accidents. Although many of these patients reported somnolence while on Pramipexole dihydrochloride tablets, some perceived that they had no warning signs such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events had been reported as late as one year after the initiation of treatment.

Somnolence is a common occurrence in patients receiving Pramipexole dihydrochloride tablets at doses above 1.5 mg/day (0.5 mg TID) for Parkinson’s disease. Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.

Before initiating treatment with Pramipexole dihydrochloride tablets, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with Pramipexole dihydrochloride tablets such as concomitant sedating medications, the presence of sleep disorders, and concomitant medications that increase Pramipexole plasma levels (e.g., cimetidine - see PRECAUTIONS, Drug Interactions). If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), Pramipexole dihydrochloride tablets should ordinarily be discontinued. If a decision is made to continue Pramipexole dihydrochloride tablets, patients should be advised to not drive and to avoid other potentially dangerous activities. While dose reduction clearly reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Symptomatic Hypotension

Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. Parkinson's disease patients, in addition, appear to have an impaired capacity to respond to an orthostatic challenge. For these reasons, Parkinson's disease patients being treated with dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk (see PRECAUTIONS, Information for Patients).

In clinical trials of Pramipexole, however, and despite clear orthostatic effects in normal volunteers, the reported incidence of clinically significant orthostatic hypotension was not greater among those assigned to Pramipexole dihydrochloride tablets than among those assigned to placebo. This result, especially with the higher doses used in Parkinson’s disease, is clearly unexpected in light of the previous experience with the risks of dopamine agonist therapy.

While this finding could reflect a unique property of Pramipexole, it might also be explained by the conditions of the study and the nature of the population enrolled in the clinical trials. Patients were very carefully titrated, and patients with active cardiovascular disease or significant orthostatic hypotension at baseline were excluded.

Hallucinations

In the three double-blind, placebo-controlled trials in early Parkinson's disease, hallucinations were observed in 9% (35 of 388) of patients receiving Pramipexole dihydrochloride tablets, compared with 2.6% (6 of 235) of patients receiving placebo. In the four double-blind, placebo-controlled trials in advanced Parkinson's disease, where patients received Pramipexole dihydrochloride tablets and concomitant levodopa, hallucinations were observed in 16.5% (43 of 260) of patients receiving Pramipexole dihydrochloride tablets compared with 3.8% (10 of 264) of patients receiving placebo. Hallucinations were of sufficient severity to cause discontinuation of treatment in 3.1% of the early Parkinson's disease patients and 2.7% of the advanced Parkinson's disease patients compared with about 0.4% of placebo patients in both populations.

Age appears to increase the risk of hallucinations attributable to Pramipexole. In the early Parkinson's disease patients, the risk of hallucinations was 1.9 times greater than placebo in patients younger than 65 years and 6.8 times greater than placebo in patients older than 65 years. In the advanced Parkinson's disease patients, the risk of hallucinations was 3.5 times greater than placebo in patients younger than 65 years and 5.2 times greater than placebo in patients older than 65 years.

Precautions

Rhabdomyolysis

A single case of rhabdomyolysis occurred in a 49-year-old male with advanced Parkinson's disease treated with Pramipexole dihydrochloride tablets. The patient was hospitalized with an elevated CPK (10,631 IU/L). The symptoms resolved with discontinuation of the medication.

Renal

Since Pramipexole is eliminated through the kidneys, caution should be exercised when prescribing Pramipexole dihydrochloride tablets to patients with renal insufficiency (see DOSAGE AND ADMINISTRATION).

Dyskinesia

Pramipexole dihydrochloride tablets may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate preexisting dyskinesia. Decreasing the dose of levodopa may ameliorate this side effect.

Retinal Pathology in Albino Rats

Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in the 2 year carcinogenicity study. While retinal degeneration was not diagnosed in pigmented rats treated for 2 years, a thinning in the outer nuclear layer of the retina was slightly greater in rats given drug compared with controls. Evaluation of the retinas of albino mice, monkeys, and minipigs did not reveal similar changes. The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved (see ANIMAL TOXICOLOGY).

Events Reported With Dopaminergic Therapy

Although the events enumerated below may not have been reported in association with the use of Pramipexole in its development program, they are associated with the use of other dopaminergic drugs. The expected incidence of these events, however, is so low that even if Pramipexole caused these events at rates similar to those attributable to other dopaminergic therapies, it would be unlikely that even a single case would have occurred in a cohort of the size exposed to Pramipexole in studies to date.

Withdrawal-Emergent Hyperpyrexia and Confusion

Although not reported with Pramipexole in the clinical development program, a symptom complex resembling the 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 antiparkinsonian therapy.

Fibrotic Complications

Although not reported with Pramipexole in the clinical development program, cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening, pericarditis, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.

Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot derived dopamine agonists can cause them is unknown.

A small number of reports have been received of possible fibrotic complications, including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis, in the post-marketing experience for Pramipexole dihydrochloride tablets. While the evidence is not sufficient to establish a causal relationship between Pramipexole dihydrochloride tablets and these fibrotic complications, a contribution of Pramipexole dihydrochloride tablets cannot be completely ruled out in rare cases.

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 when using Pramipexole dihydrochloride tablets for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Information for Patients (Also see Patient Package Insert)

Patients should be instructed to take Pramipexole dihydrochloride tablets only as prescribed.

Patients should be alerted to the potential sedating effects associated with Pramipexole dihydrochloride tablets, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Since somnolence is a frequent adverse event with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with Pramipexole dihydrochloride tablets to gauge whether or not it affects their mental and/or motor performance adversely. Patients should be advised that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Because of possible additive effects, caution should be advised when patients are taking other sedating medications or alcohol in combination with Pramipexole dihydrochloride tablets and when taking concomitant medications that increase plasma levels of Pramipexole (e.g., cimetidine).

Patients should be informed that hallucinations can occur and that the elderly are at a higher risk than younger patients with Parkinson's disease.

There have been reports of patients experiencing intense urges to gamble, increased sexual urges, and other intense urges and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone, that are generally used for the treatment of Parkinson’s disease, including Pramipexole dihydrochloride. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with Pramipexole dihydrochloride. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking Pramipexole dihydrochloride. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Pramipexole dihydrochloride.

Patients may develop postural (orthostatic) hypotension, with or without symptoms such as dizziness, nausea, fainting or blackouts, and sometimes, sweating. Hypotension may occur more frequently during initial therapy. Accordingly, patients should be cautioned against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with Pramipexole dihydrochloride tablets.

Because the teratogenic potential of Pramipexole has not been completely established in laboratory animals, and because experience in humans is limited, patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy (see PRECAUTIONS, Pregnancy).

Because of the possibility that Pramipexole may be excreted in breast milk, patients should be advised to notify their physicians if they intend to breast-feed or are breast-feeding an infant.

If patients develop nausea, they should be advised that taking Pramipexole dihydrochloride tablets with food may reduce the occurrence of nausea.

Laboratory Tests

During the development of Pramipexole dihydrochloride tablets, no systematic abnormalities on routine laboratory testing were noted. Therefore, no specific guidance is offered regarding routine monitoring; the practitioner retains responsibility for determining how best to monitor the patient in his or her care.

Drug Interactions

Carbidopa/levodopa: Carbidopa/levodopa did not influence the pharmacokinetics of Pramipexole in healthy volunteers (N = 10). Pramipexole did not alter the extent of absorption (AUC) or the elimination of carbidopa/levodopa, although it caused an increase in levodopa Cmax by about 40% and a decrease in Tmax from 2.5 to 0.5 hours.

Selegiline: In healthy volunteers (N = 11), selegiline did not influence the pharmacokinetics of Pramipexole.

Amantadine: Population pharmacokinetic analyses suggest that amantadine may slightly decrease the oral clearance of Pramipexole.

Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in Pramipexole AUC and a 40% increase in half-life (N = 12).

Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the anionic transporter, did not noticeably influence Pramipexole pharmacokinetics (N = 12).

Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of Pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of Pramipexole.

CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect Pramipexole elimination because Pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 µM, indicating that Pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the clinical dose of 4.5 mg/day (1.5 mg TID).

Dopamine antagonists: Since Pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of Pramipexole dihydrochloride tablets.

Drug/Laboratory Test Interactions

There are no known interactions between Pramipexole dihydrochloride tablets and laboratory tests.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies with Pramipexole have been conducted in mice and rats. Pramipexole was administered in the diet to Chbb:NMRI mice at doses of 0.3, 2, and 10 mg/kg/day [0.3, 2.2, and 11 times the Maximum Recommended Human Dose (MRHD) (MRHD of 1.5 mg TID on a mg/m2 basis)]. Pramipexole was administered in the diet to Wistar rats at 0.3, 2, and 8 mg/kg/day (plasma AUCs were 0.3, 2.5, and 12.5 times the AUC in humans at the MRHD). No significant increases in tumors occurred in either species.

Pramipexole was not mutagenic or clastogenic in a battery of assays, including the in vitro Ames assay, V79 gene mutation assay for HGPRT mutants, chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus assay.

In rat fertility studies, Pramipexole at a dose of 2.5 mg/kg/day (5 times the MRHD on a mg/m2 basis), prolonged estrus cycles and inhibited implantation. These effects were associated with reductions in serum levels of prolactin, a hormone necessary for implantation and maintenance of early pregnancy in rats.

Pregnancy

Teratogenic Effects

Pregnancy category C

When Pramipexole was given to female rats throughout pregnancy, implantation was inhibited at a dose of 2.5 mg/kg/day (5 times the MRHD on a mg/m2 basis). Administration of 1.5 mg/kg/day of Pramipexole to pregnant rats during the period of organogenesis (gestation days 7 through 16) resulted in a high incidence of total resorption of embryos. The plasma AUC in rats at this dose was 4 times the AUC in humans at the MRHD. These findings are thought to be due to the prolactin-lowering effect of Pramipexole, since prolactin is necessary for implantation and maintenance of early pregnancy in rats (but not rabbits or humans). Because of pregnancy disruption and early embryonic loss in these studies, the teratogenic potential of Pramipexole could not be adequately evaluated. There was no evidence of adverse effects on embryo-fetal development following administration of up to 10 mg/kg/day to pregnant rabbits during organogenesis (plasma AUC was 71 times that in humans at the MRHD). Postnatal growth was inhibited in the offspring of rats treated with 0.5 mg/kg/day (approximately equivalent to the MRHD on a mg/m2 basis) or greater during the latter part of pregnancy and throughout lactation.

There are no studies of Pramipexole in human pregnancy. Because animal reproduction studies are not always predictive of human response, Pramipexole should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Nursing Mothers

A single-dose, radio-labeled study showed that drug-related materials were excreted into the breast milk of lactating rats. Concentrations of radioactivity in milk were three to six times higher than concentrations in plasma at equivalent time points.

Other studies have shown that Pramipexole treatment resulted in an inhibition of prolactin secretion in humans and rats.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Pramipexole, a decision should be made as to whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and efficacy of Pramipexole dihydrochloride tablets in pediatric patients has not been established.

Geriatric Use

Pramipexole total oral clearance was approximately 30% lower in subjects older than 65 years compared with younger subjects, because of a decline in Pramipexole renal clearance due to an age-related reduction in renal function. This resulted in an increase in elimination half-life from approximately 8.5 hours to 12 hours. In clinical studies with Parkinson’s disease patients, 38.7% of patients were older than 65 years. There were no apparent differences in efficacy or safety between older and younger patients, except that the relative risk of hallucination associated with the use of Pramipexole dihydrochloride tablets was increased in the elderly.

ADVERSE EVENTS

Parkinson’s Disease

During the premarketing development of Pramipexole, patients with either early or advanced Parkinson's disease were enrolled in clinical trials. Apart from the severity and duration of their disease, the two populations differed in their use of concomitant levodopa therapy. Patients with early disease did not receive concomitant levodopa therapy during treatment with Pramipexole; those with advanced Parkinson's disease all received concomitant levodopa treatment. Because these two populations may have differential risks for various adverse events, this section will, in general, present adverse-event data for these two populations separately.

Because the controlled trials performed during premarketing development all used a titration design, with a resultant confounding of time and dose, it was impossible to adequately evaluate the effects of dose on the incidence of adverse events.

Early Parkinson's Disease

In the three double-blind, placebo-controlled trials of patients with early Parkinson's disease, the most commonly observed adverse events (> 5%) that were numerically more frequent in the group treated with Pramipexole dihydrochloride tablets were nausea, dizziness, somnolence, insomnia, constipation, asthenia, and hallucinations.

Approximately 12% of 388 patients with early Parkinson's disease and treated with Pramipexole dihydrochloride tablets who participated in the double-blind, placebo-controlled trials discontinued treatment due to adverse events compared with 11% of 235 patients who received placebo. The adverse events most commonly causing discontinuation of treatment were related to the nervous system (hallucinations [3.1% on Pramipexole dihydrochloride tablets vs 0.4% on placebo]; dizziness [2.1% on Pramipexole dihydrochloride tablets vs 1% on placebo]; somnolence [1.6% on Pramipexole dihydrochloride tablets vs 0% on placebo]; extrapyramidal syndrome [1.6% on Pramipexole dihydrochloride tablets vs 6.4% on placebo]; headache and confusion [1.3% and 1.0%, respectively, on Pramipexole dihydrochloride tablets vs 0% on placebo]); and gastrointestinal system (nausea [2.1% on Pramipexole dihydrochloride tablets vs 0.4% on placebo]).

Adverse-event incidence in controlled clinical studies in early Parkinson's disease

Table 1 lists treatment-emergent adverse events that occurred in the double-blind, placebo-controlled studies in early Parkinson's disease that were reported by ≥ 1% of patients treated with Pramipexole dihydrochloride tablets and were numerically more frequent than in the placebo group. In these studies, patients did not receive concomitant levodopa. Adverse events were usually mild or moderate in intensity.

The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse-event incidence rate in the population studied.

Table 1: Treatment-Emergent Adverse-Event* Incidence in Double-Blind, Placebo-Controlled Trials in Early Parkinson's Disease (Events ≥ 1% of Patients Treated With Pramipexole Dihydrochloride Tablets and Numerically More Frequent Than in the Placebo Group)

* Patients may have reported multiple adverse experiences during the study or at discontinuation; thus, patients may be included in more than one category.
Body System/Adverse Event	Pramipexole Dihydrochloride Tablets	Placebo
	N = 388	N = 235
Body as a Whole
Asthenia	14	12
General edema	5	3
Malaise	2	1
Reaction unevaluable	2	1
Fever	1	0
Digestive System
Nausea	28	18
Constipation	14	6
Anorexia	4	2
Dysphagia	2	0
Metabolic & Nutritional System
Peripheral edema	5	4
Decreased weight	2	0
Nervous System
Dizziness	25	24
Somnolence	22	9
Insomnia	17	12
Hallucinations	9	3
Confusion	4	1
Amnesia	4	2
Hypesthesia	3	1
Dystonia	2	1
Akathisia	2	0
Thinking abnormalities	2	0
Decreased libido	1	0
Myoclonus

Corona Udder Butter

Generic Name: petrolatum ointment

Dosage Form: FOR ANIMAL USE ONLY
Corona Udder Butter Active Ingredient: Petrolatum 68%

Corona Udder Butter is a lanolin-enriched moisturizing ointment formulated to protect and help relieve the discomfort of chapped, sore, raw udder and teats.

to protect and relieve the discomfort of chapped sore, raw udder and teats.

As in normal pre-milking sanitation, wash teats and udder thoroughly before milking to avoid residues in milk. After milking, wash with warm water, throughly strip out milk, pat dry with clean towel and spread Udder Butter generously over the affected area, letting the emollients remain to soothe, soften and protect.

Continue to use routinely as described, applying as needed until condition is alleviated, rawness and chapping are relieved, resiliency and comfort of teats and udder are restored.

Udder Butter's smooth, easy-spreading formula lubricates and softens painful, cracked, tender, or abraded udder and teats. Massaged into the affected areas, Udder Butter eases the discomfort of sensitive skin and helps restore moisture balance to painful, parched surfaces, providing comfort and healthy suppleness. soothing Udder Butter protects and helps support the natural healing of affective areas.

Also contains: Castor Oil, Emulsifier, Fragrance, lanolin, Neatsfoot Oil, and Oxyquinoline

Caution: If conditions persist or become worse, or in case of deep wounds, or serious burns, consult your veterinarian

For external use only.

Keep out of the reach of children.

For horses and other animals: as soothing protection for chapped, windburned face and muzzle; as an emollient for minor irritations, abrasions, and burns; as a hoof hointment, helping maintain hoof health, moisture balance, supplenss.

For veterinary use only.

SUMMIT INDUSTRIES, INC., PO BOX 7329 MARIETTA, GA 30065

800-241-6996

www.coronaproducts.com

Corona Udder Butter  petrolatum  ointment

Product Information Product Type OTC ANIMAL DRUG NDC Product Code (Source) 12090-0031 Route of Administration TOPICAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PETROLATUM (PETROLATUM) PETROLATUM 68 g  in 100 g

Inactive Ingredients Ingredient Name Strength CASTOR OIL   LANOLIN   OXYQUINOLINE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 12090-0031-1 198.5 g In 1 TUBE None 2 12090-0031-6 907.2 g In 1 JAR None 3 12090-0031-5 3061.8 g In 1 PAIL None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
unapproved drug other		11/08/2010

Labeler - SUMMIT INDUSTRIES, INC. (003279189)

Registrant - SUMMIT INDUSTRIES, INC. (003279189)

Revised: 11/2010SUMMIT INDUSTRIES, INC.