Sinemet Product Monograph

RECENT MAJOR LABEL CHANGES

Not applicable.

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES............................................................................................ 2

TABLE OF CONTENTS .............................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION ..................................................................... 4

1 INDICATIONS .............................................................................................................. 4

1.1 Pediatrics .......................................................................................................... 4

1.2 Geriatrics........................................................................................................... 4

2 CONTRAINDICATIONS ................................................................................................. 4

3 SERIOUS WARNINGS AND PRECAUTIONS BOX ............................................................ 5

4 DOSAGE AND ADMINISTRATION................................................................................. 5

4.1 Dosing Considerations ....................................................................................... 5

4.2 Recommended Dose and Dosage Adjustment..................................................... 6

4.3 Reconstitution ................................................................................................... 7

4.4 Administration................................................................................................... 7

4.5 Missed Dose ...................................................................................................... 8

5 OVERDOSAGE ............................................................................................................. 8

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 8

7 WARNINGS AND PRECAUTIONS .................................................................................. 9

7.1 Special Populations .......................................................................................... 11

7.1.1 Pregnant Women ....................................................................................... 11

7.1.2 Breast-feeding............................................................................................ 11

7.1.3 Pediatrics ................................................................................................... 11

7.1.4 Geriatrics ................................................................................................... 12

8 ADVERSE REACTIONS ................................................................................................ 12

8.1 Adverse Reaction Overview.............................................................................. 12

8.2 Clinical Trial Adverse Reactions ........................................................................ 12

8.2.1 Clinical Trial Adverse Reactions – Pediatrics ................................................ 14

8.3 Less Common Clinical Trial Adverse Reactions .................................................. 15

8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics .......................... 15

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ...................................................................................................... 15

8.5 Post-Market Adverse Reactions........................................................................ 15

9 DRUG INTERACTIONS................................................................................................ 15

9.1 Drug Interactions Overview.............................................................................. 15

9.2 Drug-Behavioural Interactions.......................................................................... 15

9.3 Drug-Drug Interactions .................................................................................... 15

9.4 Drug-Food Interactions .................................................................................... 16

9.5 Drug-Herb Interactions .................................................................................... 16

9.6 Drug-Laboratory Test Interactions .................................................................... 16

10 CLINICAL PHARMACOLOGY ....................................................................................... 17

10.1 Mechanism of Action.................................................................................. 17

10.2 Pharmacodynamics .................................................................................... 17

10.3 Pharmacokinetics ....................................................................................... 17

11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 18

12 SPECIAL HANDLING INSTRUCTIONS........................................................................... 18

PART II: SCIENTIFIC INFORMATION ...................................................................................... 19

13 PHARMACEUTICAL INFORMATION............................................................................ 19

14 CLINICAL TRIALS........................................................................................................ 19

14.1 Trial Design and Study Demographics ......................................................... 19

14.2 Study Results ............................................................................................. 19

14.3 Comparative Bioavailability Studies ............................................................ 19

14.4 Immunogenicity ......................................................................................... 19

15 MICROBIOLOGY ........................................................................................................ 20

16 NON-CLINICAL TOXICOLOGY ..................................................................................... 20

17 SUPPORTING PRODUCT MONOGRAPHS.................................................................... 24

PATIENT MEDICATION INFORMATION ................................................................................. 25

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

SINEMET® (levodopa and carbidopa) is indicated for the treatment of Parkinson’s disease.

SINEMET® is not recommended for the treatment of drug-induced extrapyramidal reactions.

1.1 Pediatrics

Pediatrics (< 18 years of age):

The safety and effectiveness of SINEMET® in patients under 18 years of age has not been established.

1.2 Geriatrics

Not applicable.

2 CONTRAINDICATIONS

• SINEMET® is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING of the product monograph.
• Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with SINEMET® (levodopa and carbidopa). These inhibitors must be discontinued at least two weeks prior to initiating therapy with SINEMET®. SINEMET® may be administered concomitantly with a MAO inhibitor with selectivity for MAO type B (e.g. selegiline HCl) (see DRUG INTERACTIONS, Drug-Drug Interactions, Psychoactive Drugs) at the manufacturer’s recommended dose which maintains selectivity for MAO type B.
• SINEMET® should not be administered to patients with clinical or laboratory evidence of uncompensated cardiovascular, endocrine, hematologic, hepatic, pulmonary (including bronchial asthma), or renal disease; or to patients with narrow angle glaucoma.
• As with levodopa, SINEMET® should not be given when administration of a sympathomimetic amine is contraindicated (e.g., epinephrine, norepinephrine or isoproterenol).
• Because levodopa may activate a malignant melanoma, SINEMET® should not be used in patients with suspicious, undiagnosed skin lesions or a history of melanoma.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• In order to reduce the incidence of adverse reactions and achieve maximal benefit, therapy with SINEMET® (levodopa and carbidopa) must be individualized and drug administration must be continuously matched to the needs and tolerance of the patient. It should be borne in mind that the therapeutic range of SINEMET® is narrower than that of levodopa alone because of its greater milligram potency. Therefore, titration and

  • adjustment of dosage should be made in small steps and the dosage ranges recommended should usually not be exceeded. The appearance of involuntary movements should be regarded as a sign of levodopa toxicity and as an indication of overdosage, requiring dose reduction. Treatment should, therefore, aim at maximal benefit without dyskinesias.
• If a patient being treated with levodopa is switched to therapy with SINEMET®, levodopa must be discontinued at least twelve hours or more before therapy with SINEMET® is initiated.
• Although the administration of carbidopa permits control of Parkinson’s disease with much lower doses of levodopa, there is no conclusive evidence at present that this is beneficial other than reducing nausea and vomiting, permitting more rapid titration, and providing a somewhat smoother response to levodopa. Carbidopa does not decrease adverse reactions due to central effects of levodopa. By permitting more levodopa to reach the brain, particularly when nausea and vomiting is not a dose-limiting factor, certain adverse CNS effects, e.g., dyskinesias, may occur at lower dosages and sooner during therapy with SINEMET® than with levodopa.
• SINEMET® tablets are available in a 4:1 ratio (SINEMET® 100/25) and in a 10:1 ratio of levodopa to carbidopa (SINEMET® 250/25). Tablets of the two ratios may be given separately or combined as needed to provide the optimal dosage.
• Dividing the tablets along the score line may not give exact equal half doses.
• Studies have shown that peripheral dopa decarboxylase is saturated by carbidopa at doses between 70 to 150 mg per day. Patients receiving less than 70 mg per day of carbidopa are more likely to experience nausea and vomiting. Experience with total daily dosages of carbidopa greater than 200 mg is limited.
• For patients who require only low doses of levodopa, e.g., less than 700 mg, SINEMET® 100/25 may be helpful.

4.2 Recommended Dose and Dosage Adjustment

• Induction of Therapy in Patients Not Receiving Levodopa

  Dosage is best initiated with one tablet of SINEMET® 100/25 three times a day. This dosage schedule provides 75 mg of carbidopa per day. Dosage may be carefully increased by one tablet every three days until the optimal dosage has been reached which does not produce dyskinesias.

  While increasing the dosage during the induction period, the doses should be divided, aiming at a frequency of dosing of at least four times a day. If further titration is necessary after a daily dosage level of six tablets of SINEMET® 100/25 has been reached, tablets of SINEMET® 250/25 may be used as needed to provide the optimal dosage.

  Usually no patient should receive more than 1500 mg of levodopa a day. Some patients, including those with postencephalitic parkinsonism, are more sensitive to levodopa and require specially careful dosage adjustment.

• Induction of Therapy in Patient Receiving Levodopa

  Levodopa must be discontinued at least twelve hours or more before SINEMET^® is started. A dosage of SINEMET® should be used that will provide approximately 20% of the previous levodopa daily dosage; this can be started in the morning after the day in which the treatment with levodopa has been stopped. For example, if a patient is receiving 4,000 mg of levodopa per day, the dosage of SINEMET® should not provide more than 750 mg of levodopa per day divided into four to six doses.

  Tablets of SINEMET® 100/25 should be used to start medication for patients requiring lower dosages of levodopa.

• Adjustment and Maintenance of Therapy

  Therapy should be individualized and adjusted according to the desired therapeutic response. At least 70 to 100 mg of carbidopa per day should be provided. When more levodopa is required, SINEMET® 250/25 should be substituted for SINEMET® 100/25. If necessary, the dosage of SINEMET® 250/25 may be increased by one tablet every day or every other day to a maximum of eight tablets a day. Experience with total daily dosages of carbidopa greater than 200 mg is limited.

  Because both therapeutic and adverse responses occur more rapidly with SINEMET® than with levodopa alone, patients should be monitored closely during the dose adjustment period. Specifically, involuntary movements will occur more rapidly with SINEMET® than with levodopa. The occurrence of involuntary movements may require dosage reduction. Blepharospasm may be a useful early sign of excess dosage in some patients.

  Current evidence indicates that other standard antiparkinsonian drugs may be continued while SINEMET® is being administered although their dosage may have to be adjusted.

  If general anesthesia is required, therapy with SINEMET® may be continued as long as the patient is permitted to take fluids and medication by mouth. If therapy is interrupted temporarily, the usual daily dosage may be administered as soon as the patient is able to take oral medication.

4.3 Reconstitution

• Not Applicable.

4.4 Administration

• Not Applicable.

4.5 Missed Dose

If a tablet is missed, it should be taken as soon as possible. If it is almost time to take the next tablet, the missed tablet should not be taken, and the normal schedule should be resumed.

5 OVERDOSAGE

Management of acute overdosage with SINEMET® (levodopa and carbidopa) is basically the same as management of acute overdosage with levodopa alone. However, pyridoxine is not effective in reversing the actions of SINEMET®.

General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered judiciously and an adequate airway maintained. Electrocardiographic monitoring should be instituted and the patient carefully observed for the possible development of arrhythmias; if required, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have taken other drugs as well as SINEMET® should be taken into consideration. To date, no experience has been reported with dialysis; hence, its value in overdosage is not known.

For up-to-date information on the management of a suspected drug overdose, the physician should consider contacting a regional Poison Control Centre.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table – Dosage Forms, Strengths, Composition and Packaging

Description

SINEMET® tablets contain levodopa and carbidopa in ratios of 4:1 and 10:1.

SINEMET®, 100/25, contains 100 mg of levodopa and 25 mg anhydrous equivalent of carbidopa. They are yellow, oval, uncoated tablets, plain on one side with “650” and a score line on the other. They are supplied in bottles of 100 tablets.

SINEMET®, 250/25, contains 250 mg of levodopa and 25 mg anhydrous equivalent of carbidopa. They are light dapple-blue, oval, uncoated tablets, plain on one side with “654” and a score line on the other. They are supplied in bottles of 100 tablets.

SINEMET® 250/25 tablets also contain FD&C Blue No. 2 Aluminum Lake. SINEMET® 100/25 tablets also contain D & C yellow No. 10 Lake.

7 WARNINGS AND PRECAUTIONS

General

When patients already receiving levodopa are switched to SINEMET®, levodopa must be discontinued for at least 12 hours or more before SINEMET® is started. SINEMET® should be substituted at a dosage that will provide approximately 20% of the previous levodopa dosage (see 4 DOSAGE AND ADMINISTRATION).

Patients who are taking SINEMET® should be instructed not to take additional levodopa unless it is prescribed by the physician.

Periodic evaluations of hepatic, hematopoietic, cardiovascular and renal function are recommended during extended therapy with SINEMET® (levodopa and carbidopa).

Physical Activity

Patients who improve while on therapy with SINEMET® should increase physical activities gradually, with caution, consistent with other medical considerations such as the presence of osteoporosis or phlebothrombosis.

Cardiovascular

Care should be exercised in administering SINEMET® to patients with a history of myocardial infarction or who have atrial, nodal, or ventricular arrhythmias. In such patients, cardiac function should be monitored with particular care during the period of initial dosage adjustment in a facility with provisions for intensive cardiac care.

Gastrointestinal

SINEMET® should be administered cautiously to patients with a history of peptic ulcer disease due to the possibility of upper gastrointestinal hemorrhage.

Neurologic

The levodopa induced involuntary movements and ‘on and off’ phenomenon may appear earlier with combination therapy.

As with levodopa, SINEMET® may cause involuntary movements and mental disturbances. These reactions are thought to be due to increased brain dopamine following administration of levodopa. Because carbidopa permits more levodopa to reach the brain and thus, more dopamine to be formed, dyskinesias may occur at lower dosages and sooner with SINEMET® than with levodopa. The occurrence of dyskinesias may require dosage reduction.

SINEMET® should be used cautiously in patients who have a history of seizures or have conditions associated with seizure or have a lowered seizure threshold.

Neuroleptic Malignant Syndrome: A symptom complex resembling the neuroleptic malignant syndrome including muscular rigidity, elevated body temperature, altered consciousness, mental changes, autonomic instability and increased serum creatine phosphokinase has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy. Therefore, patients should be observed carefully when the dosage of SINEMET® is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.

Psychomotor Performance:] Certain side effects that have been reported with SINEMET® may affect some patients’ ability to drive or operate machinery.

Given the reported cases of somnolence and sudden onset of sleep (not necessarily preceded by somnolence), physicians should caution patients about the risk of operating hazardous machinery, including driving motor vehicles, while taking SINEMET®. If drowsiness or sudden onset of sleep should occur, patients should be informed to refrain from driving or operating machines and to immediately contact their physician (see 6 WARNINGS AND PRECAUTIONS, SERIOUS WARNINGS AND PRECAUTIONS BOX , Sudden Onset of Sleep).

Ophthalmologic

Use in Patients with Glaucoma: Pupillary dilatation and activation of latent Horner’s syndrome have been reported during levodopa treatment. Patients with chronic wide angle glaucoma should therefore be treated cautiously with SINEMET®. The intraocular pressure should be well controlled and the patient monitored carefully for changes in intraocular pressure during therapy.

Peri-Operative Considerations

If general anesthesia is required, therapy with SINEMET® may be continued as long as the patient is permitted to take fluids and medication by mouth. If therapy is interrupted temporarily, the usual daily dosage may be administered as soon as the patient is able to take oral medication (see 4 DOSAGE AND ADMINISTRATION, Adjustment and Maintenance of Therapy).

Psychiatric

Patients should be monitored carefully for the development of depression with suicidal tendencies. Patients with past or current psychoses should be treated with caution.

Behavioural Changes: Patients and caregivers should be advised to adhere to dosage instructions given by the physician. Patients should be regularly monitored for the development of impulse control disorders. Patients and caregivers should be made aware that behavioral symptoms of impulse control disorders, including pathological (compulsive) gambling, hypersexuality, increased libido, compulsive spending/buying, and binge/compulsive eating, have been reported in patients treated with dopaminergic agonists and/or other dopaminergic treatments for Parkinson’s disease, including SINEMET® (see 8 ADVERSE REACTIONS). Literature and postmarketing reports have described a very rare addictive pattern of dopamine replacement therapy, in which patients use doses in excess of those required to control their motor symptoms. Review of treatment is recommended if such symptoms develop.

Hallucinations: Hallucinations and confusion are known side effects of treatment with dopaminergic agents, including levodopa. Patients should be aware of the fact that hallucinations (mostly visual) can occur.

Skin

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 healthcare providers are advised to monitor for melanomas frequently and on a regular basis when using SINEMET® for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

7.1 Special Populations

7.1.1 Pregnant Women

Although the effects of SINEMET® on human pregnancy and lactation are unknown, both levodopa and combinations of carbidopa and levodopa have caused visceral and skeletal malformations in rabbits (see 16 NON-CLINICALTOXICOLOGY, Teratologic and Reproductive Studies). Therefore, use of SINEMET® in women of child-bearing potential requires that the anticipated benefits of the drug be weighed against possible hazards to the mother and to the fetus.

7.1.2 Breast-feeding

It is not known whether carbidopa is excreted in human milk. In a study of one nursing mother with Parkinson’s disease, excretion of levodopa in breast milk was reported. SINEMET® should not be given to nursing mothers unless the anticipated benefits to the mother outweigh the potential hazards to the infant.

7.1.3 Pediatrics

Pediatrics (< 18 years of age): The safety of SINEMET^® in patients under 18 years of age has not been established.

Monitoring and Laboratory Tests

Periodic evaluations of hepatic, hematopoietic, cardiovascular and renal function are recommended during extended therapy with SINEMET® (levodopa and carbidopa).

SINEMET® may cause a false-positive reaction for urinary ketone bodies when a tape test is used for determination of ketonuria. False-negative tests may result with the use of glucose-oxidase methods of testing for glucosuria. Caution should be exercised when interpreting the plasma and urine levels of catecholamines and their metabolites in patients on levodopa or levodopa-carbidopa therapy (see 9 DRUG INTERACTIONS, Drug-Laboratory Test Interactions).

7.1.4 Geriatrics

Not applicable.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Adverse reactions that occur frequently in patients receiving SINEMET are those due to the central neuropharmacologic activity of dopamine. These reactions usually can be diminished by dosage reduction. The most common side effects are dyskinesias, including choreiform, dystonic, and other involuntary movements and nausea. Muscle twitching and blepharospasm may be taken as early signs to consider dosage reduction.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

The most common serious adverse reactions occurring with SINEMET® (levodopa and carbidopa) are dyskinesias, including choreiform, dystonic and other involuntary movements, and nausea. Other serious adverse reactions are mental changes including paranoid ideation and psychotic episodes, depression with or without development of suicidal tendencies, and dementia. Convulsions also have occurred; however, a causal relationship with SINEMET® has not been established.

Other adverse reactions reported in clinical trials or in post-marketing experience include:

Body as a whole:

Syncope, chest pain, anorexia, asthenia.

Cardiovascular:

Cardiac irregularities and/or palpitation, hypotension, orthostatic effects including hypotensive episodes, hypertension, phlebitis.

Gastrointestinal:

Vomiting, gastrointestinal bleeding, development of duodenal ulcer, diarrhea, dark saliva, constipation, dyspepsia, dry mouth, taste alterations.

Hematologic:

Leukopenia, hemolytic and non-hemolytic anemia, thrombocytopenia, agranulocytosis.

Hypersensitivity:

Angioedema, urticaria, pruritus, Henoch-Schönlein purpura, bullous lesions (including pemphigus-like reactions).

Musculoskeletal:

Back pain, shoulder pain, muscle cramps.

Nervous System/Psychiatric:

Neuroleptic malignant syndrome (see 7 WARNINGS AND PRECAUTIONS), bradykinetic episodes (the “on-off” phenomenon), dizziness, somnolence including very rarely excessive daytime somnolence and sudden sleep onset episodes, paresthesia, psychotic episodes including delusions, hallucinations and paranoid ideation, dream abnormalities including nightmares, insomnia, headache, depression with or without development of suicidal tendencies, dementia, agitation, confusion.

In post-marketing use, pathological (compulsive) gambling, increased libido, hypersexuality, compulsive spending/buying, and binge/compulsive eating have been reported with dopamine agonists and/or other dopaminergic treatments, and rarely in patients treated with levodopa, including SINEMET^® (see 7 WARNINGS AND PRECAUTIONS)

Respiratory:

Dyspnea, upper respiratory infection.

Skin:

Alopecia, rash, increased sweating, dark sweat, malignant melanoma (see 2 CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS, Skin).

Urogenital:

Dark urine, urinary frequency, urinary tract infection.

Other adverse reactions that have been reported with levodopa alone and with various levodopa-carbidopa formulations, and may occur with SINEMET^® are:

Body as a whole:

Fatigue.

Cardiovascular:

Myocardial infarction.

Gastrointestinal:

Sialorrhea, dysphagia, bruxism, hiccups, abdominal pain and distress, flatulence, burning sensation of tongue, gastrointestinal pain, heart burn.

Metabolic:

Weight gain or loss, edema.

Musculoskeletal:

Leg pain.

Nervous System/Psychiatric:

Decreased mental acuity, disorientation, ataxia, numbness, increased hand tremor, muscle twitching, blepharospasm (which may be taken as an early sign of excess dosage, consideration of dosage reduction may be made at this time), trismus, activation of latent Horner’s syndrome, anxiety, euphoria, falling and gait abnormalities, extrapyramidal disorder, nervousness, memory impairment, peripheral neuropathy.

Respiratory:

Pharyngeal pain, cough.

Skin:

Flushing.

Special Senses:

Diplopia, blurred vision, dilated pupils, and oculogyric crises.

Urogenital:

Urinary retention, urinary incontinence, priapism.

Miscellaneous:

Faintness, hoarseness, malaise, hot flashes, sense of stimulation, bizarre breathing patterns.

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

Not applicable.

8.3 Less Common Clinical Trial Adverse Reactions

Not applicable.

8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics

Not applicable.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Laboratory tests which have been reported to be abnormal are alkaline phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, bilirubin, blood urea nitrogen, creatinine, uric acid, and positive Coomb’s test.

Decreased hemoglobin and hematocrit; elevated serum glucose; and white blood cells, bacteria and blood in the urine have been reported.

Decreased white blood cell count and serum potassium; protein and glucose in urine have been reported with levodopa alone and with various levodopa-carbidopa formulations and may occur with SINEMET^®.

8.5 Post-Market Adverse Reactions

Information is found with clinical trial adverse drug reactions under Subsection 8.2.

9 DRUG INTERACTIONS

9.1 Drug Interactions Overview

Caution is advised when SINEMET® is used with other concomitant medications to avoid drug interactions.

9.2 Drug-Behavioural Interactions

See 7 WARNINGS AND PRECAUTIONS, Psychiatric, Behavioural Changes.

9.3 Drug-Drug Interactions

Caution should be exercised when the following drugs are administered concomitantly with SINEMET^®:

Antihypertensive Drugs: Symptomatic postural hypotension can occur when SINEMET^® is added to the treatment of a patient receiving antihypertensive drugs. Therefore, when therapy with SINEMET^® is started, dosage adjustment of the antihypertensive drug may be required.

Psychoactive Drugs: Dopamine D2 receptor antagonists (e.g. phenothiazines, butyrophenones, and risperidone) may reduce the therapeutic effects of levodopa. The beneficial effects of levodopa in Parkinson’s disease have been reported to be reversed by phenytoin and papaverine. Patients taking these drugs with SINEMET^® should be carefully observed for loss of antiparkinsonian effect.

Concomitant therapy with selegiline and levodopa-carbidopa preparations may be associated with severe orthostatic hypotension not attributable to levodopa-carbidopa alone (see 2 CONTRAINDICATIONS).

There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and SINEMET^®. For patients receiving monoamine oxidase inhibitors, see 2 CONTRAINDICATIONS.

Dopamine Depleting Agents: Use of SINEMET^® with dopamine-depleting agents (e.g., reserpine¹ and tetrabenazine) or other drugs known to deplete monoamine stores is not recommended as reduction in patient response to levodopa may occur.

Isoniazid: Isoniazid may reduce the therapeutic effects of levodopa.

Anesthetics: When general anesthesia is required, SINEMET^® should be discontinued the night before. Therapy with SINEMET^® may be continued as soon as the patient is able to take medication by mouth.

Iron: Studies have demonstrated that ferrous sulphate decreases the bioavailability of carbidopa and/or levodopa. Because this interaction may be due to the formation of drug-iron complexes, other iron supplement formulations and iron-containing multivitamins may have similar effects.

Metoclopramide: Although metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying, metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic properties.

9.4 Drug-Food Interactions

Since levodopa competes with certain amino acids, the absorption of levodopa may be impaired in some patients on a high protein diet.

9.5 Drug-Herb Interactions

Not applicable.

9.6 Drug-Laboratory Test Interactions

SINEMET^® may cause a false-positive reaction for urinary ketone bodies when a tape test is used for determination of ketonuria. This reaction will not be altered by boiling the urine specimen. False-negative tests may result with the use of glucose-oxidase methods of testing for glucosuria.

Cases of falsely diagnosed pheochromocytoma in patients with levodopa-carbidopa therapy have been reported very rarely. Caution should be exercised when interpreting the plasma and urine levels of catecholamines and their metabolites in patients on levodopa or levodopa-carbidopa therapy.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

The symptoms of Parkinson’s disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson’s disease because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor of dopamine, does cross the blood-brain barrier, and is converted to dopamine in the basal ganglia. This is thought to be the mechanism whereby levodopa relieves the symptoms of Parkinson’s disease.

10.2 Pharmacodynamics

When levodopa is administered orally it is rapidly converted to dopamine by decarboxylation in peripheral tissues so that only a small portion of a given dose is transported unchanged to the central nervous system. For this reason, large doses of levodopa are required for adequate therapeutic effect and these may often be attended by nausea and other adverse reactions, some of which are attributable to dopamine formed in peripheral tissues.

Carbidopa inhibits decarboxylation of peripheral levodopa. It does not cross the blood-brain barrier and does not affect the metabolism of levodopa within the central nervous system. Since its decarboxylase inhibiting activity is limited to peripheral tissues, administration of carbidopa with levodopa makes more levodopa available for transport to the brain. Combined therapy with levodopa and carbidopa reduces the amount of levodopa required for optimum therapeutic benefit by about 75–80%, permits an earlier response to therapy, and also reduces the incidence of nausea, vomiting and cardiac arrhythmias. Combined therapy, however, does not decrease adverse reactions due to central effects of levodopa.

10.3 Pharmacokinetics

At steady state, the bioavailability of carbidopa from SINEMET^® tablets is approximately 99% relative to the concomitant administration of carbidopa and levodopa. Since levodopa competes with certain aminoacids, the absorption of levodopa may be impaired in some patients on a high protein diet.

Following simultaneous administration of carbidopa and levodopa in man, both plasma levels and plasma half-life of levodopa are markedly increased over those found when the same dosage of levodopa is given alone, while plasma levels of dopamine and homovanillic acid are reduced or do not change. Nevertheless, the plasma levels vary greatly between patients.

The plasma half-life of levodopa is about 50 minutes, without carbidopa. When carbidopa and levodopa are administered together, the half-life of levodopa is increased to about 1.5 hours.

In clinical pharmacologic studies, simultaneous administration of carbidopa and levodopa produced greater urinary excretion of levodopa in proportion to the excretion of dopamine than administration of the two drugs at separate times.

Pyridoxine hydrochloride (vitamin B₆), in oral doses of 10 mg to 25 mg, may reverse the effects of levodopa by increasing the rate of aromatic amino acid decarboxylation. Carbidopa inhibits this action of pyridoxine.

11 STORAGE, STABILITY AND DISPOSAL

Tablets should be stored at room temperature (15 °C–30 °C). Store in tightly closed container, protected from light and moisture.

12 SPECIAL HANDLING INSTRUCTIONS

Not applicable.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:	levodopa and	carbidopa
Chemical name:	(-)-3-(3,4-Dihydroxyphenyl)-L-alanine	(-)-L-α-Hydrazino-3,4- dihydroxy- α- methylhydrocinnamic acid mono- hydrate.
Molecular formula:	C9H11NO4	C10H14N2O4 • H2O
Molecular mass:	197.2	244.3
	Tablet content is expressed in terms of anhydrous carbidopa, which has a molecular weight of 226.3.
Structural formula:
Physicochemical properties:	Levodopa, an aromatic amino acid, is a white, crystalline compound, slightly soluble in water.	Carbidopa, an inhibitor of aromatic amino acid decarboxylase, is a white, crystalline compound, slightly soluble in water.

14 CLINICAL TRIALS

14.1 Trial Design and Study Demographics

Not applicable.

14.2 Study Results

Not applicable.

14.3 Comparative Bioavailability Studies

Not applicable.

14.4 Immunogenicity

Not applicable.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:

Summary of Acute Oral Toxicity Data

A. Carbidopa

B. Levodopa

C. Carbidopa/Levodopa (1:1)

D. Carbidopa/Levodopa (1:3)

^xx Sum of individual doses of carbidopa/levodopa

A – Adult

W – Weanling

I – Infant

The preceding table summarizes the acute toxicity data for carbidopa and levodopa alone and in combination. Mortality usually occurred in 12 hours with carbidopa and 30 minutes with levodopa. With the combination of carbidopa and levodopa, deaths occurred between 30 minutes and 24 hours at high doses and up to 12 days with lower doses. The toxicity did not continue to decrease with drug ratios above 1:3.

In oral subacute toxicity studies, carbidopa is more toxic for dogs than for monkeys or rats. Following doses of 45 mg/kg/day for six weeks, dogs exhibited anorexia, emesis, tarry stools, diarrhea, dry nose and/or gums, fine muscular tremors, weight loss, prolonged clotting and prothrombin times, bilirubinuria and decreases in total leukocytes, total protein and albumin, and SGOT activity. The increased toxicity in dogs appeared to be due to pyridoxine-deficiency, since concurrent administration of pyridoxine decreased the toxicity of carbidopa. Doses up to 135 mg/kg/day produced no drug-related effects in the monkey and only flaccidity in some rats. Slight centrolobular vacuolization of hepatocytes in two rats and significantly higher mean kidney weights were observed in the highest dosage group.

Oral toxicity studies with doses of levodopa up to 1000 mg/kg/day for 13 weeks indicated no treatment-related effects in monkeys. In rats, treatment-related morphologic changes occurred in salivary glands (hypertrophy of acinar cells) and adrenals (cytoplasmic rarefaction of the zona glomerulosa) at all dosage levels, in kidneys of rats receiving 500 and 1000 mg/kg/day (tubular necrosis with regeneration and necrosis respectively) and in the stomach (focal necrosis of the superficial epithelium) of some rats in the high dosage group. A statistically significant leucocytosis and increase in heart and kidney weights occurred in females of this latter group; males had a significant increase in heart and liver weights and a decrease in growth rate. Clinical signs of toxicity included ptyalism, piloerection, hyperventilation with intermittent dyspnea and decreased activity.

Combinations of carbidopa and levodopa in respective doses of 30/30, 30/60, and 30/120 mg/kg/day were given orally for 14 weeks to monkeys and for 13 weeks to rats. Signs of toxicity in monkeys were related to dosage and indicated that coadministration enhanced the pharmacologic activity of levodopa. In the rat, the apparent degree of potentiation of levodopa by carbidopa appeared to be less.

Three dosage ratios of carbidopa and levodopa were given orally to monkeys and rats for 54 weeks. Dosages of 10/20 mg/kg/day had no apparent physical effects while hyperactivity occurred in monkeys at dosages of 10/50 and 10/100 mg/kg/day, and continued for 32 weeks with the higher dose. Muscular incoordination and weakness were observed until the twenty-second week with the 10/100 mg/kg/day dose. Pathologic studies did not show any morphologic changes. Rats that received 10/50 and 10/100 mg/kg/day had a decrease in normal activity and displayed abnormal body positions. The higher dose caused excessive salivation. There was a decrease in body weight gain. Morphological changes, where present, were those noted with levodopa alone.

Acute oral interaction studies in mice demonstrated that pre-treatment with pharmacological doses (1 mg/kg) of benztropine mesylate or trihexyphenidyl hydrochloride did not affect the acute toxicity of carbidopa, levodopa or a 1:3 mixture of carbidopa:levodopa.

Higher doses (24–184 mg/kg) increased the acute toxicity of carbidopa and the combination but not of levodopa. Pre-treatment with an MAO inhibitor (phenelzine) resulted in a five-fold increase in acute toxicity of the mixture and a four-fold increase in toxicity of levodopa with no change in toxicity of carbidopa. Synergism between a 1:10 mixture of carbidopa:levodopa and amantadine was indicated by increased toxicity in the female mouse. However, no synergism was demonstrated between therapeutic doses of amantadine and carbidopa, levodopa or a 1:10 mixture.

Reproductive and Developmental Toxicology:

Teratologic and Reproductive Studies

The incidences of malformations of the heart and great vessels were 0 of 105, 1 of 94, and 6 of 81 fetuses from rabbits given 75, 125 or 250 mg of levodopa/kg/day respectively by the oral route, indicating a dose-dependent teratogenic effect. Anomalies included septal defects, constricted or missing ductus arteriosus, enlarged aortic arches, fused aortas and pulmonary arches, and transpositions.

The same types of malformations were also induced in fetuses from rabbits given doses of various combinations of levodopa and carbidopa, but they were not observed when carbidopa was given alone. The malformations, possibly drug-related, were also seen in one mouse fetus from a dam which had received 500 mg of levodopa/kg/day. No drug- induced malformations were observed in fetuses of mice given various combinations of the two drugs or in the offspring of rats given carbidopa. The significance of heart and great vessel malformations in one stunted fetus from a female mouse given the lowest dose of carbidopa (30 mg/kg/day) and in one stillborn pup from a female rat given the mid-dose of the drug combination (10 mg of carbidopa/kg plus 50 mg of levodopa/kg/day) is questionable; both offspring also had other external, cranial and skeletal malformations.

Other effects on reproduction associated with combination treatments in the rabbit included decreased maternal weight gains and fetal weights, and increased resorptions, and incidences of various skeletal anomalies, especially of vertebral centra and skull bones. In mice given the combination product, only a decrease in fetal weight occurred. In rats, none of these effects were observed; the maximal dose administered was 10 mg of carbidopa/kg plus 100 mg of levodopa/kg/day.

DETAILED PHARMACOLOGY

Levodopa: Pharmacological experiments in various species of animals have shown that levodopa produced increased motor activity, aggressive behaviour and electroencephalographic alerting behaviour. However, occasional sedation and ataxia have also been reported in some animal species. Levodopa also reverses the reserpine induced Parkinson-like effects in animals. Cardiovascular studies in dogs and cats have shown that levodopa increases the catecholamine levels in the brain which has been evident in an initial increase in blood pressure followed by a secondary decrease in blood pressure. The changes in blood pressure appear to correlate with the changes in renal function. Biochemical studies in vivo as well as in vitro have demonstrated that levodopa is decarboxylated to dopamine in many tissues. Levodopa crosses the blood-brain barrier and elevates the dopamine concentration in the brain. The dopamine formed can be degraded to dihydroxyphenylacetic and homovanillic acids which are the two major metabolites in the urine. Dopamine may also be converted to noradrenaline, in which case the major metabolites are vanillylmandelic acid and dihydroxymandelic acid.

Carbidopa: In the absence of biogenic amine precursors, carbidopa is singularly inert pharmacologically. Carbidopa lacks effects upon blood pressure in normal, neurogenic hypertensive, or renal hypertensive dogs. It also does not affect heart rate, exhibit ganglionic, adrenergic, or peripheral anticholinergic properties, or influence renal electrolyte excretion in this species. In mice or rats, carbidopa does not appreciably affect gastric secretion, nor gastric or colonic motility. The compound does not antagonize electroshock or pentylenetetrazol-induced convulsions in mice; neither does it exhibit analgesic activity or affect fixed interval-fixed ratio reinforcement behaviour in rats. Overt behavioural effects have not been observed with carbidopa in the rhesus monkey, dog, rat, mouse or pigeon. The dose levels of carbidopa used in the latter investigations were in excess of those necessary to inhibit aromatic amino acid decarboxylase or to alter the actions of levodopa. The studies suggest that carbidopa, when administered alone at dose levels effective in inhibiting aromatic amino acid decarboxylases, lacks appreciable effects upon the cardiovascular, gastrointestinal, renal, or central nervous systems.

Levodopa and Carbidopa Combination: Decarboxylation within peripheral organs and the walls of the brain capillaries limits the portion of an administered dose of levodopa accessible to most central nervous structures. Inhibition of peripheral aromatic amino acid decarboxylase enhances the accumulation of levodopa in the blood and increases the amount of this amino acid available to the brain. If brain decarboxylase is not also inhibited, the result is a marked accumulation of dopamine in the brain. Such a mechanism explains the marked enhancement of brain Dopa and dopamine levels which results when levodopa is administered in combination with carbidopa which does not penetrate central nervous system structures even when administered in high doses. Levodopa increases motor activity and irritability, and antagonizes reserpine-induced hypothermia, suppressed locomotion, and ptosis in mice. All these effects are enhanced two-to-six fold by pre-treatment with carbidopa. Increased motor activity induced by levodopa in rats also is enhanced by pre-treatment with carbidopa. In contrast, levodopa-induced vomiting is decreased significantly in dogs and pigeons by pre-treatment with carbidopa.

Metabolism: Carbidopa is incompletely absorbed in the rat, dog and rhesus monkey. Following oral administration of a dose of ¹⁴C labelled drug, the percentages of radioactive carbon excreted in urine and feces were:

Urines contained both unchanged drug and metabolites.

Tissue distribution of radioactivity in rats, sacrificed one hour after an intravenous dose of 20 mg/kg of ¹⁴C-carbidopa, showed the major portion of radioactivity to be concentrated in the kidneys, lungs, small intestine, and liver; in descending order. None was detected in the brain. Following an oral dose of radioactive labelled carbidopa to healthy subjects and to patients with Parkinson’s disease, maximal plasma levels of radioactivity were reached in two to four hours in the healthy subjects and in one and one-half to five hours in the patients. Approximately equal quantities were excreted in the urine and the feces by both groups. Comparison of urinary metabolites in healthy subjects and patients indicated that the drug is metabolized to the same degree in both. Urinary excretion of unchanged drug was essentially complete in seven hours and represented 35% of the total urinary radioactivity. Only metabolites were present thereafter. In monkeys, an oral dose of levodopa given one hour after a dose of radioactive labelled carbidopa had no significant effect on the absorption or excretion of carbidopa. Peak plasma levels of radioactivity were achieved in the same period of time and disappeared at the same rate as with carbidopa alone.

17 SUPPORTING PRODUCT MONOGRAPHS

Not applicable.