Pro-Levocarb Product Monograph

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TABLE OF CONTENTS

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

RECENT MAJOR LABEL CHANGES Not applicable .......................................................................... 2

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

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

1 INDICATIONS ..................................................................................................................... 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

4.4 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 ................................................................................................................ 11

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

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

8.2 Clinical Trial Adverse Reactions .............................................................................. 12 8.3 Less Common Clinical Trial Adverse Reactions ....................................................... 12

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other

Quantitative Data ................................................................................................... 13

8.5 Post-Market Adverse Reactions ............................................................................. 14

9 DRUG INTERACTIONS ...................................................................................................... 14

9.1 Serious Drug Interactions ....................................................................................... 14

9.2 Drug Interactions Overview ................................................................................... 14

9.3 Drug-Behavioural Interactions ............................................................................... 14

9.4 Drug-Drug Interactions ........................................................................................... 14

9.5 Drug-Food Interactions .......................................................................................... 16

9.6 Drug-Herb Interactions .......................................................................................... 17

Interactions with herbal products have not been established. ....................................... 17

9.7 Drug-Laboratory Test Interactions ......................................................................... 17

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

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

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

10.3 Pharmacokinetics ................................................................................................... 18

11 STORAGE, STABILITY AND DISPOSAL ............................................................................... 20

12 SPECIAL HANDLING INSTRUCTIONS ................................................................................. 20

PART II: SCIENTIFIC INFORMATION ............................................................................................. 21

13 PHARMACEUTICAL INFORMATION .................................................................................. 21

14 CLINICAL TRIALS............................................................................................................... 22

14.1 Trial Design and Study Demographics .................................................................... 22

14.2 Comparative Bioavailability Studies ....................................................................... 22

15 MICROBIOLOGY ............................................................................................................... 24

16 NON-CLINICAL TOXICOLOGY ............................................................................................ 24

17 SUPPORTING PRODUCT MONOGRAPHS .......................................................................... 27

PATIENT MEDICATION INFORMATION ........................................................................................ 28 PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

PRO-LEVOCARB (levodopa and carbidopa tablets) is indicated for the treatment of Parkinson's disease.

PRO-LEVOCARB is not recommended for the treatment of drug-induced extrapyramidal reactions.

1.1 Pediatrics

Pediatrics (<18 years of age): The safety and effectiveness of levodopa and carbidopa in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics (>65 years of age): Evidence from clinical studies and experience with levodopa and carbidopa combinations suggest that use in the geriatric population is not associated with differences in safety or effectiveness (see 4.2 Recommended Dose and Dosage Adjustment, Geriatrics).

2 CONTRAINDICATIONS

PRO-LEVOCARB 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
• taking nonselective monoamine oxidase inhibitors (MAOIs). These inhibitors must be discontinued at least two weeks prior to initiating therapy with PRO-LEVOCARB. PRO-LEVOCARB may be administered concomitantly with a MAO inhibitor with selectivity for MAO type B (e.g. selegiline HCl) (see 9.4 Drug-Drug Interactions) at the manufacturer’s recommended dose which maintains selectivity for MAO type B.
• with clinical or laboratory evidence of uncompensated cardiovascular, endocrine, hematologic, hepatic, pulmonary (including bronchial asthma), or renal disease.
• with narrow angle glaucoma.
• for whom administration of a sympathomimetic amine is contraindicated (e.g., epinephrine, norepinephrine, amphetamines or isoproterenol).
• with suspicious, undiagnosed skin lesions or a history of melanoma; because levodopa may activate a malignant melanoma.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

• Sudden Onset of Sleep

Patients receiving treatment with levodopa and carbidopa and other dopaminergic agents have reported suddenly falling asleep while engaged in activities of daily living, including the driving of a car, which has sometimes resulted in accidents. Although some of the patients reported somnolence while on levodopa and carbidopa, others perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event.

Physicians should alert patients of the reported cases of sudden onset of sleep, bearing in mind that these events are NOT limited to initiation of therapy. Patients should also be advised that sudden onset of sleep has occurred without warning signs and should be specifically asked about factors that may increase the risk with PRO-LEVOCARB such as concomitant medications or the presence of sleep disorders. 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 PRO-LEVOCARB. 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.

Episodes of falling asleep while engaged in activities of daily living have also been reported in patients taking other dopaminergic agents, therefore, symptoms may not be alleviated by substituting these products.

While 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.

Currently, the precise cause of this event is unknown. It is known that many Parkinson’s disease patients experience alterations in sleep architecture, which results in excessive daytime sleepiness or spontaneous dozing, and that dopaminergic agents can also induce sleepiness.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• In order to reduce the incidence of adverse reactions and achieve maximal benefit, therapy with PRO-LEVOCARB 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 PRO-LEVOCARB 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 PRO-LEVOCARB, levodopa must be discontinued at least twelve hours or more before therapy with PRO-LEVOCARB is initiated. PRO-LEVOCARB should be substituted at a dosage that will provide approximately 20% of the previous levodopa dosage (see 4.2 Recommended Dose and Dosage Adjustment, Adults, Induction of Therapy in Patients Receiving Levodopa).

  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 PRO-LEVOCARB than with levodopa.

• Dividing the tablets along the score line may not give exact equal half doses (see 4.4

  Administration).

• 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.

4.2 Recommended Dose and Dosage Adjustment

General

PRO-LEVOCARB tablets are available in a 4:1 ratio (PRO-LEVOCARB 100 mg/25 mg) and in a 10:1 ratio of levodopa to carbidopa (PRO-LEVOCARB 100 mg/10 mg and 250 mg/25 mg). Tablets of the two ratios may be given separately or combined as needed to provide the optimal dosage.

Adults

Induction of Therapy in Patients Not Receiving Levodopa

• Dosage is best initiated with one tablet of PRO-LEVOCARB 100 mg / 25 mg 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 PRO-LEVOCARB 100 mg / 25 mg has been reached, tablets of PRO-LEVOCARB 100 mg / 10 mg or 250 mg / 25mg 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 post encephalitic parkinsonism, are more sensitive to levodopa and require specially careful dosage adjustment.

Induction of Therapy in Patients Receiving Levodopa

• Levodopa must be discontinued at least twelve hours or more before PRO-LEVOCARB is started. A dosage of PRO-LEVOCARB 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 PRO-LEVOCARB should not provide more than 750 mg of levodopa per day divided into four to six doses.
• PRO-LEVOCARB 100 mg / 25 mg tablets 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 a greater proportion of carbidopa is required, one tablet of PRO-LEVOCARB 100 mg / 25 mg may be substituted for each tablet of PRO-LEVOCARB 100 mg / 10 mg. When more levodopa is required, PRO-LEVOCARB 250 mg / 25 mg should be substituted for PRO-LEVOCARB 100 mg / 25 mg or 100 mg / 10 mg. If necessary, the dosage of PRO-LEVOCARB 250 / 25 may be increased by one tablet every day or every other day to a maximum of eight tablets a day.

• For patients who require only low doses of levodopa, e.g., less than 700 mg, PRO-LEVOCARB

  100 mg / 25 mg may be helpful.

• Experience with total daily dosages of carbidopa greater than 200 mg is limited.
• Because both therapeutic and adverse responses occur more rapidly with levodopa and carbidopa than with levodopa alone, patients should be monitored closely during the dose adjustment period. Specifically, involuntary movements will occur more rapidly with levodopa and carbidopa 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 levodopa and carbidopa is being administered although their dosage may have to be adjusted.
• If general anesthesia is required, therapy with PRO-LEVOCARB 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.
• Patients who are taking PRO-LEVOCARB should be instructed not to take additional levodopa unless it is prescribed by the physician.

Pediatrics (<18 years of age): Health Canada has not authorized an indication for pediatric use.

Geriatrics (>65 years of age): Doses for all patients including geriatric population are individually adjusted by titration (see 4.1 Dosing Considerations; 4.2 Recommended Dose and Dosage Adjustment, Adults).

4.4 Administration

Patients should be advised to swallow PRO-LEVOCARB tablets whole with fluids, and NOT to chew, divide or crush.

4.5 Missed Dose

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

5 OVERDOSAGE

Management of acute overdosage with PRO-LEVOCARB is basically the same as management of acute overdosage with levodopa alone. However, pyridoxine is not effective in reversing the actions of PRO-LEVOCARB.

General supportive measures should be employed. 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 PRO-LEVOCARB should be taken into consideration. To date, no experience has been reported with dialysis, hence, its value in overdosage is not known.

For management of a suspected drug overdose, contact your regional poison control centre.

6 DOSAGE FORMS, STRENGTHS COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

PRO-LEVOCARB 100 mg / 10 mg: Blue, oval, biconvex tablet. Engraved APO bisect 100 over 10 on one side, other side plain, contains 100 mg of levodopa and 10 mg of carbidopa expressed as anhydrous carbidopa. Available in bottles of 100 and 500.

PRO-LEVOCARB 100 mg / 25 mg: Yellow, oval, biconvex tablet. Engraved APO bisect 100 over 25 on one side, other side plain, contains 100 mg of levodopa and 25 mg of carbidopa expressed as anhydrous carbidopa. Available in bottles of 100 and 500.

PRO-LEVOCARB 250 mg / 25 mg: Blue, oval, biconvex tablet. Engraved APO bisect 250 over 25 on one side, other side plain, contains 250 mg of levodopa and 25 mg of carbidopa expressed as anhydrous carbidopa. Available in bottles of 100 and 500.

7 WARNINGS AND PRECAUTIONS

See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX

General

Physical Activity: Patients who improve while on therapy with PRO-LEVOCARB 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 PRO-LEVOCARB 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.

Driving and Operating Machinery

Certain side effects that have been reported with levodopa and carbidopa 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 PRO-LEVOCARB. 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 3 SERIOUS WARNINGS AND PRECAUTIONS BOX).

Gastrointestinal

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

Monitoring and Laboratory Tests

Periodic evaluations of hepatic, hematopoietic, cardiovascular and renal function are recommended during extended therapy with PRO-LEVOCARB.

PRO-LEVOCARB 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 9.7 Drug-Laboratory Test Interactions)

Neurologic

Dyskinesia: The levodopa induced involuntary movements and 'on and off' phenomenon may appear earlier with combination therapy.

As with levodopa, PRO-LEVOCARB 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 PRO-LEVOCARB than with levodopa. The occurrence of dyskinesias may require dosage reduction.

Seizures: PRO-LEVOCARB 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 PRO-LEVOCARB is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.

Ophthalmologic

Use in Patients with Glaucoma: PRO-LEVOCARB is contraindicated in patients with narrow angle glaucoma (see 2 CONTRAINDICATIONS). 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 PRO-LEVOCARB. 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 PRO-LEVOCARB 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 4.2 Recommended Dose and Dosage Adjustment).

Psychiatric

Depression: 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 behavioural 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 levodopa and carbidopa (see 8.2 Clinical Trial Adverse Reactions). Literature and post marketing 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: Because levodopa may activate a malignant melanoma, PRO-LEVOCARB is contraindicated in patients with suspicious, undiagnosed skin lesions or a history of melanoma (see 2 CONTRAINDICATIONS). 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 PRO-LEVOCARB 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 levodopa and carbidopa 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-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology). Therefore, use of PRO-LEVOCARB in women of childbearing 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. PRO-LEVOCARB 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 and effectiveness of levodopa and carbidopa has not been established in pediatric patients; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

Geriatrics (>65 years of age): Evidence from clinical studies and experience with levodopa and carbidopa combinations suggest that use in the geriatric population is not associated with differences in safety or effectiveness (see 4.2 Recommended Dose and Dosage Adjustment, Geriatrics).

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Adverse reactions that occur frequently in patients receiving levodopa and carbidopa are those due to the central neuro pharmacologic 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 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 levodopa and carbidopa has not been established.

8.3 Less Common Clinical Trial Adverse Reactions

Other adverse reactions reported in clinical trials or in post-marketing experience include (see also 8.5 Post-Market Adverse Reactions):

Blood and lymphatic system: Leukopenia, hemolytic and non-hemolytic anemia, thrombocytopenia, agranulocytosis.

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

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

General disorders and administration site conditions: asthenia.

Immune System: angioedema, urticaria.

Metabolism and nutrition: anorexia.

Musculoskeletal and connective tissue: Back pain, shoulder pain, muscle cramps. Neoplasms benign, malignant and unspecified (including cysts and polyps): malignant melanoma (see 2 CONTRAINDICATIONS; 7 WARNINGS AND PRECAUTIONS, Skin, Melanoma).

Nervous System: Neuroleptic malignant syndrome (see 7 WARNINGS AND PRECAUTIONS, Neurologic), bradykinetic episodes (the “on-off” phenomenon), dizziness, somnolence including very rarely excessive daytime somnolence and sudden sleep onset episodes, paresthesia, headache, insomnia, dementia, agitation, confusion.

Psychiatric: Psychotic episodes including delusions, hallucinations and paranoid ideation, dream abnormalities including nightmares, depression with or without development of suicidal tendencies.

Renal and urinary: Dark urine, urinary frequency, urinary tract infection.

Respiratory: Dyspnea, upper respiratory infection.

Skin and subcutaneous tissue: Alopecia, rash, increased sweating, dark sweat, pruritus, bullous lesions (including pemphigus-like reactions).

Vascular: Henoch-Schönlein purpura.

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

Cardiac: Myocardial infarction.

Eye: Diplopia, blurred vision, dilated pupils, oculogyric crisis.

Gastrointestinal: Sialorrhea, dysphagia, bruxism, hiccups, abdominal pain and distress, flatulence, burning sensation of tongue, gastrointestinal pain, heartburn.

General disorders and administration site conditions: Fatigue, malaise, hot flashes, sense of stimulation.

Metabolism and nutrition: Weight gain or loss, edema.

Musculoskeletal and connective tissue: Leg pain, muscle twitching.

Nervous System: Decreased mental acuity, disorientation, ataxia, numbness, increased hand tremor, 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, falling and gait abnormalities, extrapyramidal disorder, memory impairment, peripheral neuropathy, faintness, hoarseness.

Psychiatric: Anxiety, euphoria, nervousness.

Renal and urinary: Urinary retention, urinary incontinence, priapism.

Respiratory: Pharyngeal pain, cough, bizarre breathing patterns.

Skin and subcutaneous tissue: Flushing.

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 PRO-LEVOCARB formulations, and may occur with PRO-LEVOCARB.

8.5 Post-Market Adverse Reactions

In post-marketing use, pathological (compulsive) gambling, increased libido, hyper sexuality, 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 levodopa and carbidopa (see 7 WARNINGS AND PRECAUTIONS, Psychiatric, Behavioural Changes).

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

Serious Drug Interactions

• Do not use PRO-LEVOCARB with nonselective monoamine oxidase inhibitors (MAOIs).

  These inhibitors must be discontinued at least two weeks prior to initiating therapy with PRO-LEVOCARB (see 2 CONTRAINDICATIONS; 9.4 Drug-Drug Interactions)

9.2 Drug Interactions Overview

Caution is advised when PRO-LEVOCARB is used with other concomitant medications to avoid drug interactions.

9.3 Drug-Behavioural Interactions

See 7 WARNINGS AND PRECAUTIONS, Psychiatric, Behavioural Changes.

9.4 Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 2 – Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

9.5 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.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

PRO-LEVOCARB 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 PRO-LEVOCARB 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 PRO-LEVOCARB 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. 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 to 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.

10.2 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.

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.

Levodopa: Pharmacological experiments in various species of animals have shown that levodopa produced increased motor activity, aggressive behaviour and electro encephalographic 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.

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: 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.

10.3 Pharmacokinetics

Absorption

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

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 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.

Distribution

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.

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.

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.

Metabolism

Levodopa: 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 dihydroxy phenylacetic and homovanillic acids which are the two major metabolites in the urine. Dopamine may also be converted to nor adrenaline, in which case the major metabolites are vanillylmandelic acid and dihydroxymandelic acid.

Elimination

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.

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 were 16% for rat, 66% for dog and 40% for monkey; and in feces were 52% for rat, 11% for dog and 32% for monkey. Urines contained both unchanged drug and metabolites.

Following an oral dose of radioactive labelled carbidopa to healthy subjects and to patients with Parkinson’s disease, 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.

11 STORAGE, STABILITY AND DISPOSAL

PRO-LEVOCARB (levodopa and carbidopa) tablets should be stored at controlled room temperature (15°C to 30°C), in well-closed containers, protected from light and moisture.

PRO-LEVOCARB Meets USP Dissolution Test 2.

12 SPECIAL HANDLING INSTRUCTIONS

None

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Levodopa

Chemical name: 1) L-Tyrosine,3-hydroxy-;

1. 2) (-)-3-(3,4-Dihydroxyphenyl)-L-alanine.

Molecular formula and

molecular mass

C₉H₁₁NO₄ and 197.19 g/mol

Structural formula:

Physicochemical

properties:

White to off white, odourless, crystalline powder. In the presence of moisture, is rapidly oxidized by atmospheric oxygen and darkens. Slightly soluble in water; freely soluble in 3N hydrochloric acid; insoluble in alcohol.

Proper name: Carbidopa

Chemical name: 1) Benzenepropanoic acid, α-hydrazino-3,4-dihydroxy-α-methyl, monohydrate, (S);

1. 2) (-)-L-α-Hydrazino-3,4-di-hydroxy-α-methylhydrocinnamic acid monohydrate.

Molecular formula and

molecular mass

C₁₀H₁₄N₂O₄.H₂O and 244.25 g/mol

Tablet content is expressed in terms of anhydrous carbidopa, which has a molecular weight of 226.3 g/mol.

Structural formula:

Physicochemical

properties:

White to creamy white, odourless or practically odourless powder. Slightly soluble in water; freely soluble in 3N hydrochloric acid; slightly soluble in methanol; practically insoluble in alcohol, in acetone, in chloroform and in ether.

14 CLINICAL TRIALS

14.1 Trial Design and Study Demographics

The clinical trial data on which the original indication was authorized is not available for PRO-LEVOCARB (levodopa and carbidopa tablets).

14.2 Comparative Bioavailability Studies

A randomized, two-way, single dose, crossover comparative bioavailability study of PRO-LEVOCARB (levodopa and carbidopa) 100 mg / 25 mg tablets (Pro Doc Ltée.) with SINEMET® 100 mg / 25 mg tablets (Merck Sharp & Dohme, Canada) was conducted in healthy, adult, male subjects under fasting conditions. Comparative bioavailability data from the 21 subjects that were included in the statistical analysis are presented in the following table:

Summary table of the comparative bioavailability data

A randomized, two-way, single dose, crossover comparative bioavailability study of PRO-LEVOCARB (levodopa and carbidopa) 250 mg / 25 mg tablets (Pro Doc Ltée.) with SINEMET® 250 mg / 25 mg tablets (Merck Sharp & Dohme, Canada) was conducted in healthy, adult, male subjects under fasting conditions. Comparative bioavailability data from the 23 subjects that were included in the statistical analysis are presented in the following table:

Summary table of the comparative bioavailability data

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology

Acute Toxicity: The following 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.

Table 3 - Summary of Acute Oral Toxicity Data

^xx Sum of individual doses of carbidopa/levodopa

A – Adult

W – Weanling

I – Infant

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 to 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.

Subacute Toxicity: 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.

Subchronic Toxicity: 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 co administration enhanced the pharmacologic activity of levodopa. In the rat, the apparent degree of potentiation of levodopa by carbidopa appeared to be less.

Chronic Toxicity: 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.

Reproductive and Developmental Toxicology

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.

17 SUPPORTING PRODUCT MONOGRAPHS

1 SINEMET^® (levodopa and carbidopa tablets, 100 mg/25 mg, and 250 mg/ 25 mg), submission control 246915, Product Monograph, Organon Canada Inc., (APR 22, 2021)

2 AURO-LEVOCARB (levodopa and carbidopa tablets, 100 mg / 10 mg, 100 mg / 25 mg, 250 mg / 25 mg), submission control 257242, Product Monograph, Auro Pharma Inc. (OCT 11, 2022)