tion of Pharmaceutical Manufacturers Representatives, is intended to ensure that such information is reliable and that the manufacturer continues to perform this important function as one of several information sources.1 Adherence to the standards of the code of marketing practice is a condition of membership in the PMAC. Other manufacturers also are encouraged to conform. Questions regarding interpretation or clarification of any provisions, or complaints of violations of the code should be referred to the office of the PMAC for action by the marketing practices review committee. Infringements will be referred to the violator for corrective action. Repeated violations will be considered a breach of the code and will be dealt with in accordance with the PMAC bylaws. P.T. TATTLE Chairman, marketing section Pharmaceutical Manufacturers Association 1110-141 Laurier Ave. Ottawa, Ont.
Reference 1. WooDs D: Informing physicians about scription drugs. Can Med Assoc 1 111: 1 67, 1974
Relief of pain by infiltration of autonomic ganglia with steroids To the editor: I report a method of treating the pain and muscle weakness associated with polyneuritis and other similarly debilitating diseases. In a previous communication (Can Med Assoc J 111: 311, 1974) I described how the peridural injection of methylprednisolone had been a most effective therapy for extensive polyneuntis superimposed on pre-existing collagen disease of my lumbar, thoracic and cervical spine. The injection of a corticosteroid, diluted in a relatively large volume of normal saline, into the peridural space resulted in an overflow that affected the autonomic ganglia along the spine. Unfortunately this therapy necessitated hospitalization and nursing care, so I devised a simpler method. I chose the cervical portion of the autonomic ganglionic chain, which contains the easily accessible superior cervical and stellate ganglia. Each stellate ganglion was infiltrated with 0.5 mL of Celestone Soluspan (a betamethasone preparation) diluted in 1.0 mL of normal saline. On the first occasion this produced severe retrosternal and subclavicular pain that lasted for approximately 48 hours. However, there was a rapid return of muscle strength in the shoulder girdle, neck and arms within 5 minutes of the injection and muscle strength returned to the pelvic area and legs approximately 30 minutes
later. This treatment was repeated seven times at 14-day intervals and resulted in total recovery of muscle strength and abolition of pain. The later infiltrations caused less pain than the first; I attribute the severe pain that ensued from the first treatment to contact of the steroid with an irritated or inflamed ganglion. As this irritation subsided with later treatments the third and subsequent treatments caused pain for only the duration of the infiltration. I also discovered that thiamin injections, which previously had not influenced the neuritis, were now effective. The same procedure was carried out in 10 patients with severe collagen disease associated with substantially reduced muscle power and in 5 patients with terminal cancer who displayed signs of cachexia. All patients were warned that severe pain would follow the first treatment. All patients demonstrated rapid restoration of muscle strength in the upper torso within 5 minutes of receiving the infiltrations, and a return of muscle strength to the legs 30 minutes later. Muscle strength of arms and thighs was checked immediately before treatment and at 5-minute intervals afterwards until strength returned. Because of the sudden return of muscle power in otherwise severely debilitated patients it was necessary that they be cautioned against excessive straining or immoderate participation in activities they had not engaged in for some time. Nursing care and physiotherapy were in less demand because of the increased strength and mobility of these patients. I found infiltration of the stellate ganglia to be most effective in treating severe motor disturbances caused by neuritic disorders of diabetic or other origin, painful conditions of the spine such as whiplash, low back pain and sciatic pain not attributable to degenerative disc disease, and pain in the weight-bearing joints. In my case severe attacks of dysphagia were terminated by infiltration of the left stellate ganglion. As far as I could determine the superior cervical ganglia mediated painful sensations from the cranium such as those of trigeminal neuralgia and migraine. When these ganglia were infiltrated with a steroid mixed with 1 mL of 2% mepivacaine the pain disappeared instantly. In all cases seven treatments given at 14-day intervals resulted in longlasting remission of symptoms. Furthermore, the optimal generalized effect produced by the regimen makes this a safe method of treatment for diabetics; the brittle diabetes from which I suffer was not influenced unduly. FRANK B. SMALL, MD 508-823 Royal Ave. sw Calgary, Alta.
Prazosin hydrochloride To the editor: I read with considerable interest the editorial 'by Dr. Pierre Biron (Can Med Assoc J 117: 996, 1977) on prazosin hydrochloride (Minipress). I agree with the Manitoba Drug Information Bulletin1 that prazosin "is not the drug of choice with which to initiate antihypertensive treatment" and that a diuretic is a preterred agent. But I cannot agree with Dr. Biron that "it is difficult to think of a good reason for initiating therapy with prazosin in a patient with newly diagnosed hypertension" because diuretics are undesirable for some patients. Prazosin alone is as efficacious as a diuretic2 or methyldopa.3 When a diuretic is an undesirable drug in uncomplicated hyperten.ion, prazosin may well be considered as the initial therapeutic agent since it does not appear to increase plasma renin activity.4 Other vasodilators do not share this advantage and excessive salt and fluid retention invariably are associated with their use. Moreover, unlike hydralazine, prazosin infrequently causes tachycardia,2 which is a distinct advantage when a /3-blocking agent is contraindicated, as in congestive heart failure. However, prazosin also combines effectively with propranolol or a diuretic,1"7 or both, and is just as efficacious as hydralazine and has fewer disturbing side effects.5 Dr. Biron referred to a paper by Cairns and Jordan8 in which they described a 32-year-old patient who suffered acute febrile polyarthritis while taking prazosin. Dr. Biron neglected to mention that this patient had a previous history of severe, multifocal, stenosing vascular disease of unknown etiology. They concluded that the polyarthritis was likely an allergic reaction to the drug. At no time were positive results from a serologic test for systemic lupus erythematosus or rheumatoid arthritis obtained. The condition rapidly resolved when therapy with prazosin was discontinued. No other cases of this nature have been observed in 8 years of experience with prazosin and some patients have taken the drugs continuously for more than 5 years. For Canada the starting dose of prazosin has been established at 0.5 mg bid or tid, the documentation of which is recorded in the product monograph supplied by the Pfizer Company Ltd. I must clarify an area of potential confusion about the use of prazosin that one of Dr. Biron's questions may have produced. Prazosin, like any other potent antihypertensive agent, should not be added to the regimen of patients "taking a full dose of chlorthalidone, clonidine or propranolol". Common sense dictates that the doses of antihypertensive agents should be reduced
CMA JOURNAL/FEBRUARY 18, 1978/VOL. 118 357
before an additional agent is prescribed. This is especially true when one is contemplating therapy with p-blockervasodilator combinations, which can produce marked reductions of blood pressure in some individuals. No hard and fast rules can be adopted except that one should always proceed with caution when polypharmacy is required in the treatment of hypertension. In conclusion, Dr. Biron states: "It is difficult to think of a good reason... for substituting it [prazosin] for better known agents that are controlling moderate or severe hypertension." Surely it is difficult to think of a good reason for substituting any drug for one that is performing satisfactorily in a given patient. JoHN B. ARMSTRONG, MD, PH Q Medical director, Pfizer Company Ltd. Kirkland, PQ
References 1. Manitoba Drug Standards and Therapeutics Committee: Prazosin (Minipress-Pfizer). Drug ml Bull 18: 1, 1977 2. Psrrs NE: The clinical evaluation of prazosin hydrochloride, a new antihypertensive agent, in Prazosin - Evaluation of a New Anti. hypertensive Agent, CoTroN DWK (ed), Amsterdam, Excerpta Medica, 1974, p 159 3. BRADLEY WF, HOFFMAN FG, Hu'rcHssoN JC, et al: Comparison of prazosin and methyl. dopa in mild to moderate hypertension; a multicenter cooperative study. Curr Ther Res 21: 28, 1977 4. HAYES JM, GRAHAM RM, O'CONNELL BP, et al: Experience with prazosin in the treatment of patients with severe hypertension. Med I
Aust 1: 562, 1976 5. Kn.tc.snsasrrv P. HLTA ASP, MYERs JB, et al: Prazosin and hydrallazine in treatment of hypertension. Clin Sci Mol Med 51 (suppl 3):
617, 1976 6. MARSHALL AJ, BARRITT DW, PococK J, et al: Evaluation of beta blockade, bendrofluazide, and prazosin in severe hypertension. Lancet 1: 271, 1977 7. BRADLEY WF: A long-term clinical trial of
prazosin, in Prazosin - Clinical Symposium
Proceedings, Postgraduate Medicine, New York, McGraw, 1975, p 95 8. CAIRNS SA, JORDAN SC: Prazosin treatment complicated by acute febrile polyarthritis. Br Med.! 2: 1424, 1976
Optometrists To the editor: During the past 5 years it has become evident that optometrists are taking over a considerable proportion of the work traditionally considered the prerogative and responsibility of physicians, specifically ophthalmologists. As a group, optometrists are exerting political lobby pressure in Ottawa to be granted the right to be entrusted with all eye care, including some surgical procedures. This situation can influence greatly medical manpower needs in Canada. Most ophthalmologists prefer to remain in this country but to do so they require the support of the rest of the profession, particularly that of general practitioners. BEvERLEY A. BURGESS, MD, DOMS 46 Lake Avenue Dr. Stoney Creek, Ont.
(levodopa and carbidopa combination) INDICATIONS Treatment of Parkinson's syndrome with exception of drug induced parkinsonism. CONTRAI NDICATIONS When a sympathomimetic amine is contraindicated; with monoamine oxidase inhibitors, which should be discontinued two weeks prior to starting SlNEMET.; in uncompensated cardiovascular, endocrine, hematologic, hepatic, pulmonary or renal disease; in narrowangle glaucoma; in patients with suspicious, undiagnosed skin lesions or a history of melanoma. WARNI NGS When given to patients receiving levodopa alone, discontinue levodopa at least 12 hours before initiating SINEMET. at a dosage that provides approximately 20% of previous levodopa. Not recommended in drug-induced extrapyramidal reactions; contraindicated in management of intention tremor and Huntington's chorea. Levodopa related central effects such as involuntary movements may occur at lower dosages and sooner, and the 'on and off' phenomenon may appear earlier with combination therapy. Monitor carefully all patients for the development of mental changes, depression with suicidal tendencies, or other serious antisocial behaviour. Cardiac function should be monitored continuously during period of initial dosage adjustment in patients with arrhythmias. Upper gastrointestinal hemorrhage is possible in patients with history of peptic ulcer. Safety of SINEMET. in patients under 18 years of age not established. Pregnancy and lactation: In women of childbearing potential, weigh benefits against risks. Should not be given to nursing mothers. Effects on human pregnancy and lactation unknown. PRECAUTIONS General: Periodic evaluations of hepatic, hematopoietic, cardiovascular and renal function recommended in extended therapy. Treat patients with history of convulsions cautiously. Physical Activity: Advise patients improved on SINEMET. to increase physical activities gradually, with caution consistent with other medical considerations. In Glaucoma: May be given cautiously to patients with wide angle glaucoma, provided intraocular pressure is well controlled and can be carefully monitored during therapy. With Antihypertensive Therapy:Assymptomatic postural hypotension has been reported occasionally, give cautiously to patients on antihypertensive drugs, checking carefully for changes in pulse rate and blood pressure. Dosage adjustment of antihypertensive drug may be required. With Psychoactive Drugs: If concomitant administration is necessary, administer psychoactive drugs with great caution and observe patients for unusual adverse reactions. With Anesthetics: Discontinue SINEMET* the night before general anesthesia and reinstitute as soon as patient can take medication orally. ADVERSE REACTIONS Most Common: Abnormal Involuntary Movements-usually diminished by dosage reduction-choreiform, dystonic and other involuntary movements. Muscle twitching and blepharospasm may be early signs of excessive dosage. Other Serious Reactions: Oscillations in performance: diurnal variations, independent oscillations in akinesia with stereotyped dyskinesias, sudden akinetic crises related to dyskinesias, aki nesia paradoxica (hypotonic freezing) and 'on and off' phenomenon. Psychiatric: paranoid ideation, psychotic episodes, depression with or without development of suicidal tendencies and dementia. Levodopa may produce hypomania when given regularly to bipolar depressed patients. Rarely convulsions (causal relationship not established). Cardiac irregularities and or palpitations, orthostatic hypotensive episodes, anorexia, nausea, vomiting and dizziness.
358 CMA JOURNAL/FEBRUARY 18, 1978/VOL. 118
Other adverse reactions that may occur: Psychiatric: increased libido with serious antisocial behaviour, euphoria, lethargy, sedation, stimulation, fatigue and malaise, confusion, insomnia, nightmares, hallucinations and delusions, agitation and anxiety. Neurologic: ataxia, faintness, impairment of gait, headache, increased hand tremor, akinetic episodes, akinesia paradoxica, increase in the frequency and duration of the oscillations in performance, torticollis, trismus, tightness of the mouth, lips or tongue, oculogyric crisis, weakness, numbness, bruxism, priapism. Gastrointestinal: constipation, diarrhea, epigastric and abdominal distress and pain, flatulence; eructation, hiccups, sialorrhea; difficulty in swallowing, bitter taste, dry mouth; duodenal ulcer; gastrointestinal bleeding; burning sensation of the tongue. Cardiovascular: arrhythmias, hypotension, nonspecific ECG changes, flushing, phlebitis. Heinatologic: hemolytic anemia, leukopenia, agranulocytosis. Dermatologic: sweating, edema, hair loss, pallor, rash, bad odor, dark sweat. Musculoskeletal: low back pain, muscle spasm and twitching, musculoskeletal pain. Respiratory: feeling of pressure in the chest, cough, hoarseness, bizarre breathing pattern, postnasal drip. Urogenital: urinary frequency, retention, incontinence, hematuria, dark urine, nocturia, and one report of interstitial nephritis. Special Senses: blurred vision, diplopia, dilated pupils, activation of latent Homers syndrome. Miscellaneous: hot flashes, weight gain or loss. Abnormalities in laboratory tests reported with levodopa alone, which may occur with SlNEMET.: Elevations of blood urea nitrogen, SGOT, SGPT, LDH, bilirubin, alkaline phosphatase or protein bound iodine. Occasional reduction in WBC, hemoglobin and hematocrit. Elevations of uric acid with colorimetric method. Positive Coombs tests reported both with SINEMET* and with levodopa alone, but hemolytic anemia extremely rare. DOSAGE SUMMARY In order to reduce the incidence of adverse reactions and achieve maximal benefit, therapy with SINEMEP must be individualized and drug administration continuously matched to the needs and tolerance of the patient. Combined therapy with SINEMETh has a narrower therapeutic range than with levodopa alone because of its greater milligram potency. Therefore, titration and adjustment of dosage should be made in small steps and recommended dosage ranges not be exceeded. Appearance of involuntary movements should be regarded as a sign of levodopa toxicity and an indication of overdosage, requiring dose reduction. Treatment should, therefore, aim at maximal benefit without dyskinesias. Therapy in Patients not receiving Levodopa: Initially '/2 tablet once or twice a day, increase by '/2 tablet every three days if desirable. An optimum dose of 3 to 5 tablets a day divided into 4 to 6 doses. Therapy in Patients receiving Levodopa: Discontinue levodopa tor at least 12 hours, then give approximately 200/o of the previous levodopa dose in 4 to 6 divided doses. FOR COMPLETE PRESCRI BING INFORMATION, PARTICULARLY DETAILS OF DOSAGE AND ADMINISTRATION, PLEASE CONSULT PRODUCT MONOGRAPH WHICH IS AVAILABLE ON REOUEST. HOW SUPPLIED Ca 8804-Tablets SINE MET. 250, dapple-blue, oval, biconvex, scored, compressed tablets coded MSD 654, each containing 25 mg of carbidopa and 250 mg of levodopa. Available in bottles of 100 and 500. .Trademark
O MERCK I&DOHME CANADA LIMITED POINTE CLAIRE QUEBEC
SNM-8-480-JA
Reference 1. WooDs D: Informing physicians about scription drugs. Can Med Assoc 1 111: 1 67, 1974
Relief of pain by infiltration of autonomic ganglia with steroids To the editor: I report a method of treating the pain and muscle weakness associated with polyneuritis and other similarly debilitating diseases. In a previous communication (Can Med Assoc J 111: 311, 1974) I described how the peridural injection of methylprednisolone had been a most effective therapy for extensive polyneuntis superimposed on pre-existing collagen disease of my lumbar, thoracic and cervical spine. The injection of a corticosteroid, diluted in a relatively large volume of normal saline, into the peridural space resulted in an overflow that affected the autonomic ganglia along the spine. Unfortunately this therapy necessitated hospitalization and nursing care, so I devised a simpler method. I chose the cervical portion of the autonomic ganglionic chain, which contains the easily accessible superior cervical and stellate ganglia. Each stellate ganglion was infiltrated with 0.5 mL of Celestone Soluspan (a betamethasone preparation) diluted in 1.0 mL of normal saline. On the first occasion this produced severe retrosternal and subclavicular pain that lasted for approximately 48 hours. However, there was a rapid return of muscle strength in the shoulder girdle, neck and arms within 5 minutes of the injection and muscle strength returned to the pelvic area and legs approximately 30 minutes
later. This treatment was repeated seven times at 14-day intervals and resulted in total recovery of muscle strength and abolition of pain. The later infiltrations caused less pain than the first; I attribute the severe pain that ensued from the first treatment to contact of the steroid with an irritated or inflamed ganglion. As this irritation subsided with later treatments the third and subsequent treatments caused pain for only the duration of the infiltration. I also discovered that thiamin injections, which previously had not influenced the neuritis, were now effective. The same procedure was carried out in 10 patients with severe collagen disease associated with substantially reduced muscle power and in 5 patients with terminal cancer who displayed signs of cachexia. All patients were warned that severe pain would follow the first treatment. All patients demonstrated rapid restoration of muscle strength in the upper torso within 5 minutes of receiving the infiltrations, and a return of muscle strength to the legs 30 minutes later. Muscle strength of arms and thighs was checked immediately before treatment and at 5-minute intervals afterwards until strength returned. Because of the sudden return of muscle power in otherwise severely debilitated patients it was necessary that they be cautioned against excessive straining or immoderate participation in activities they had not engaged in for some time. Nursing care and physiotherapy were in less demand because of the increased strength and mobility of these patients. I found infiltration of the stellate ganglia to be most effective in treating severe motor disturbances caused by neuritic disorders of diabetic or other origin, painful conditions of the spine such as whiplash, low back pain and sciatic pain not attributable to degenerative disc disease, and pain in the weight-bearing joints. In my case severe attacks of dysphagia were terminated by infiltration of the left stellate ganglion. As far as I could determine the superior cervical ganglia mediated painful sensations from the cranium such as those of trigeminal neuralgia and migraine. When these ganglia were infiltrated with a steroid mixed with 1 mL of 2% mepivacaine the pain disappeared instantly. In all cases seven treatments given at 14-day intervals resulted in longlasting remission of symptoms. Furthermore, the optimal generalized effect produced by the regimen makes this a safe method of treatment for diabetics; the brittle diabetes from which I suffer was not influenced unduly. FRANK B. SMALL, MD 508-823 Royal Ave. sw Calgary, Alta.
Prazosin hydrochloride To the editor: I read with considerable interest the editorial 'by Dr. Pierre Biron (Can Med Assoc J 117: 996, 1977) on prazosin hydrochloride (Minipress). I agree with the Manitoba Drug Information Bulletin1 that prazosin "is not the drug of choice with which to initiate antihypertensive treatment" and that a diuretic is a preterred agent. But I cannot agree with Dr. Biron that "it is difficult to think of a good reason for initiating therapy with prazosin in a patient with newly diagnosed hypertension" because diuretics are undesirable for some patients. Prazosin alone is as efficacious as a diuretic2 or methyldopa.3 When a diuretic is an undesirable drug in uncomplicated hyperten.ion, prazosin may well be considered as the initial therapeutic agent since it does not appear to increase plasma renin activity.4 Other vasodilators do not share this advantage and excessive salt and fluid retention invariably are associated with their use. Moreover, unlike hydralazine, prazosin infrequently causes tachycardia,2 which is a distinct advantage when a /3-blocking agent is contraindicated, as in congestive heart failure. However, prazosin also combines effectively with propranolol or a diuretic,1"7 or both, and is just as efficacious as hydralazine and has fewer disturbing side effects.5 Dr. Biron referred to a paper by Cairns and Jordan8 in which they described a 32-year-old patient who suffered acute febrile polyarthritis while taking prazosin. Dr. Biron neglected to mention that this patient had a previous history of severe, multifocal, stenosing vascular disease of unknown etiology. They concluded that the polyarthritis was likely an allergic reaction to the drug. At no time were positive results from a serologic test for systemic lupus erythematosus or rheumatoid arthritis obtained. The condition rapidly resolved when therapy with prazosin was discontinued. No other cases of this nature have been observed in 8 years of experience with prazosin and some patients have taken the drugs continuously for more than 5 years. For Canada the starting dose of prazosin has been established at 0.5 mg bid or tid, the documentation of which is recorded in the product monograph supplied by the Pfizer Company Ltd. I must clarify an area of potential confusion about the use of prazosin that one of Dr. Biron's questions may have produced. Prazosin, like any other potent antihypertensive agent, should not be added to the regimen of patients "taking a full dose of chlorthalidone, clonidine or propranolol". Common sense dictates that the doses of antihypertensive agents should be reduced
CMA JOURNAL/FEBRUARY 18, 1978/VOL. 118 357
before an additional agent is prescribed. This is especially true when one is contemplating therapy with p-blockervasodilator combinations, which can produce marked reductions of blood pressure in some individuals. No hard and fast rules can be adopted except that one should always proceed with caution when polypharmacy is required in the treatment of hypertension. In conclusion, Dr. Biron states: "It is difficult to think of a good reason... for substituting it [prazosin] for better known agents that are controlling moderate or severe hypertension." Surely it is difficult to think of a good reason for substituting any drug for one that is performing satisfactorily in a given patient. JoHN B. ARMSTRONG, MD, PH Q Medical director, Pfizer Company Ltd. Kirkland, PQ
References 1. Manitoba Drug Standards and Therapeutics Committee: Prazosin (Minipress-Pfizer). Drug ml Bull 18: 1, 1977 2. Psrrs NE: The clinical evaluation of prazosin hydrochloride, a new antihypertensive agent, in Prazosin - Evaluation of a New Anti. hypertensive Agent, CoTroN DWK (ed), Amsterdam, Excerpta Medica, 1974, p 159 3. BRADLEY WF, HOFFMAN FG, Hu'rcHssoN JC, et al: Comparison of prazosin and methyl. dopa in mild to moderate hypertension; a multicenter cooperative study. Curr Ther Res 21: 28, 1977 4. HAYES JM, GRAHAM RM, O'CONNELL BP, et al: Experience with prazosin in the treatment of patients with severe hypertension. Med I
Aust 1: 562, 1976 5. Kn.tc.snsasrrv P. HLTA ASP, MYERs JB, et al: Prazosin and hydrallazine in treatment of hypertension. Clin Sci Mol Med 51 (suppl 3):
617, 1976 6. MARSHALL AJ, BARRITT DW, PococK J, et al: Evaluation of beta blockade, bendrofluazide, and prazosin in severe hypertension. Lancet 1: 271, 1977 7. BRADLEY WF: A long-term clinical trial of
prazosin, in Prazosin - Clinical Symposium
Proceedings, Postgraduate Medicine, New York, McGraw, 1975, p 95 8. CAIRNS SA, JORDAN SC: Prazosin treatment complicated by acute febrile polyarthritis. Br Med.! 2: 1424, 1976
Optometrists To the editor: During the past 5 years it has become evident that optometrists are taking over a considerable proportion of the work traditionally considered the prerogative and responsibility of physicians, specifically ophthalmologists. As a group, optometrists are exerting political lobby pressure in Ottawa to be granted the right to be entrusted with all eye care, including some surgical procedures. This situation can influence greatly medical manpower needs in Canada. Most ophthalmologists prefer to remain in this country but to do so they require the support of the rest of the profession, particularly that of general practitioners. BEvERLEY A. BURGESS, MD, DOMS 46 Lake Avenue Dr. Stoney Creek, Ont.
(levodopa and carbidopa combination) INDICATIONS Treatment of Parkinson's syndrome with exception of drug induced parkinsonism. CONTRAI NDICATIONS When a sympathomimetic amine is contraindicated; with monoamine oxidase inhibitors, which should be discontinued two weeks prior to starting SlNEMET.; in uncompensated cardiovascular, endocrine, hematologic, hepatic, pulmonary or renal disease; in narrowangle glaucoma; in patients with suspicious, undiagnosed skin lesions or a history of melanoma. WARNI NGS When given to patients receiving levodopa alone, discontinue levodopa at least 12 hours before initiating SINEMET. at a dosage that provides approximately 20% of previous levodopa. Not recommended in drug-induced extrapyramidal reactions; contraindicated in management of intention tremor and Huntington's chorea. Levodopa related central effects such as involuntary movements may occur at lower dosages and sooner, and the 'on and off' phenomenon may appear earlier with combination therapy. Monitor carefully all patients for the development of mental changes, depression with suicidal tendencies, or other serious antisocial behaviour. Cardiac function should be monitored continuously during period of initial dosage adjustment in patients with arrhythmias. Upper gastrointestinal hemorrhage is possible in patients with history of peptic ulcer. Safety of SINEMET. in patients under 18 years of age not established. Pregnancy and lactation: In women of childbearing potential, weigh benefits against risks. Should not be given to nursing mothers. Effects on human pregnancy and lactation unknown. PRECAUTIONS General: Periodic evaluations of hepatic, hematopoietic, cardiovascular and renal function recommended in extended therapy. Treat patients with history of convulsions cautiously. Physical Activity: Advise patients improved on SINEMET. to increase physical activities gradually, with caution consistent with other medical considerations. In Glaucoma: May be given cautiously to patients with wide angle glaucoma, provided intraocular pressure is well controlled and can be carefully monitored during therapy. With Antihypertensive Therapy:Assymptomatic postural hypotension has been reported occasionally, give cautiously to patients on antihypertensive drugs, checking carefully for changes in pulse rate and blood pressure. Dosage adjustment of antihypertensive drug may be required. With Psychoactive Drugs: If concomitant administration is necessary, administer psychoactive drugs with great caution and observe patients for unusual adverse reactions. With Anesthetics: Discontinue SINEMET* the night before general anesthesia and reinstitute as soon as patient can take medication orally. ADVERSE REACTIONS Most Common: Abnormal Involuntary Movements-usually diminished by dosage reduction-choreiform, dystonic and other involuntary movements. Muscle twitching and blepharospasm may be early signs of excessive dosage. Other Serious Reactions: Oscillations in performance: diurnal variations, independent oscillations in akinesia with stereotyped dyskinesias, sudden akinetic crises related to dyskinesias, aki nesia paradoxica (hypotonic freezing) and 'on and off' phenomenon. Psychiatric: paranoid ideation, psychotic episodes, depression with or without development of suicidal tendencies and dementia. Levodopa may produce hypomania when given regularly to bipolar depressed patients. Rarely convulsions (causal relationship not established). Cardiac irregularities and or palpitations, orthostatic hypotensive episodes, anorexia, nausea, vomiting and dizziness.
358 CMA JOURNAL/FEBRUARY 18, 1978/VOL. 118
Other adverse reactions that may occur: Psychiatric: increased libido with serious antisocial behaviour, euphoria, lethargy, sedation, stimulation, fatigue and malaise, confusion, insomnia, nightmares, hallucinations and delusions, agitation and anxiety. Neurologic: ataxia, faintness, impairment of gait, headache, increased hand tremor, akinetic episodes, akinesia paradoxica, increase in the frequency and duration of the oscillations in performance, torticollis, trismus, tightness of the mouth, lips or tongue, oculogyric crisis, weakness, numbness, bruxism, priapism. Gastrointestinal: constipation, diarrhea, epigastric and abdominal distress and pain, flatulence; eructation, hiccups, sialorrhea; difficulty in swallowing, bitter taste, dry mouth; duodenal ulcer; gastrointestinal bleeding; burning sensation of the tongue. Cardiovascular: arrhythmias, hypotension, nonspecific ECG changes, flushing, phlebitis. Heinatologic: hemolytic anemia, leukopenia, agranulocytosis. Dermatologic: sweating, edema, hair loss, pallor, rash, bad odor, dark sweat. Musculoskeletal: low back pain, muscle spasm and twitching, musculoskeletal pain. Respiratory: feeling of pressure in the chest, cough, hoarseness, bizarre breathing pattern, postnasal drip. Urogenital: urinary frequency, retention, incontinence, hematuria, dark urine, nocturia, and one report of interstitial nephritis. Special Senses: blurred vision, diplopia, dilated pupils, activation of latent Homers syndrome. Miscellaneous: hot flashes, weight gain or loss. Abnormalities in laboratory tests reported with levodopa alone, which may occur with SlNEMET.: Elevations of blood urea nitrogen, SGOT, SGPT, LDH, bilirubin, alkaline phosphatase or protein bound iodine. Occasional reduction in WBC, hemoglobin and hematocrit. Elevations of uric acid with colorimetric method. Positive Coombs tests reported both with SINEMET* and with levodopa alone, but hemolytic anemia extremely rare. DOSAGE SUMMARY In order to reduce the incidence of adverse reactions and achieve maximal benefit, therapy with SINEMEP must be individualized and drug administration continuously matched to the needs and tolerance of the patient. Combined therapy with SINEMETh has a narrower therapeutic range than with levodopa alone because of its greater milligram potency. Therefore, titration and adjustment of dosage should be made in small steps and recommended dosage ranges not be exceeded. Appearance of involuntary movements should be regarded as a sign of levodopa toxicity and an indication of overdosage, requiring dose reduction. Treatment should, therefore, aim at maximal benefit without dyskinesias. Therapy in Patients not receiving Levodopa: Initially '/2 tablet once or twice a day, increase by '/2 tablet every three days if desirable. An optimum dose of 3 to 5 tablets a day divided into 4 to 6 doses. Therapy in Patients receiving Levodopa: Discontinue levodopa tor at least 12 hours, then give approximately 200/o of the previous levodopa dose in 4 to 6 divided doses. FOR COMPLETE PRESCRI BING INFORMATION, PARTICULARLY DETAILS OF DOSAGE AND ADMINISTRATION, PLEASE CONSULT PRODUCT MONOGRAPH WHICH IS AVAILABLE ON REOUEST. HOW SUPPLIED Ca 8804-Tablets SINE MET. 250, dapple-blue, oval, biconvex, scored, compressed tablets coded MSD 654, each containing 25 mg of carbidopa and 250 mg of levodopa. Available in bottles of 100 and 500. .Trademark
O MERCK I&DOHME CANADA LIMITED POINTE CLAIRE QUEBEC
SNM-8-480-JA
