Prenatal diagnosis of genetic disease To the editor: In the past it was th aim of doctors to attempt to cure oi at least improve the health of theji patients. Now a new approach is beinh promulgated in the prenatal diagnosi. of genetic disease (N.E. Simpson anc colleagues, Can Med Assoc J 115: 739 1976). The aim is to kill those affectec by disease. Amniocentesis is performec because it is still not considered righ to kill the infant after birth. But wher the medical profession has been prop erly brainwashed, postnatal sacrifice 01 the deviant or abnormal will seem jus; as obvious a solution. The authors of the collaborative re port are pressing for amniocentesis ir all pregnant women over 35 years olc - evidently a vast "make-work" pro. ject. For those at risk of bearing chil dren with genetic or chromosoma disease it would be more logical to ad vise against pregnancy rather than foi amniocentesis, a procedure that is like ly to increase the population of reces sive carriers. Mi. NEWMAN, MD, FRCP[C St. Boniface General Hospita Winnipeg, Man
To the editor: Dr. Newman has sug gested that the authors of the collabo rative study of prenatal diagnosis 01 genetic disease are pressing for al mothers over 35 years of age to hav prenatal diagnosis as a "make-work' project. I am sure that all of us wh were involved in the study had n such thing in mind and in fact hav been stretched to the limit of our re sources to try to meet the demand frori the women themselves. A small per centage of pregnant women over 3. years of age (about 1 to 15% depend ing on the province) (Fig. 1 in the col laborative study) shows that the de mand has been increasing sharply. Dr. Newman also suggests that w. should be advising against pregnanc. rather than "killing" the abnorma fetuses. None of us "advise" eithe prenatal diagnosis or therapeutic abor tion; we attempt to inform the familie: of their risks and available options an help them make a decision in the ligh of their perception of the burden 0: the disease in question, the degree o' their desire to have more children am their religious or ethical beliefs. Thi data from the collaborative stud' show that only 5% of the pregnancie: of women who underwent amniocen tesis for prenatal diagnosis were selec tively aborted, that the proceduri served as reassurance for the parent: of the fetus, and that in some case; amniocentesis may have prevente( ha.uitw
ii..rfrwmpe
because of fear that the fetus was defective, when the fetus was in fact normal. Only 3% of all women undergoing prenatal diagnosis do so because of biochemical disease - those Dr. Newman suggests may increase the number of carriers in the population. Furthermore, each biochemical disease is extremely rare and the possible slight increase in gene frequencies for these diseases will not substantially increase the number of homozygotes. It is understandable that the main aim of doctors is to attempt to cure or at least improve the health of their patients, as Dr. Newman states. It is surely also important that doctors attempt to prevent disease; this, in the instances of our patients (the parents), will alleviate a great deal of suffering. NANCY E. SIMPSON, PH D, FCCMG Professor and chairman Division of medical genetics Department of pediatrics Queen's University Kingston, Ont.
Antabuse implants: placebo treatment for alcoholism? To the editor: Since the introduction of disulfiram (Antabuse) in 1948, routine use of this agent in the treatment of alcoholism has become widespread. Although there are numerous reports on the beneficial effects of its oral administration, careful reviews of this literature reveal that the therapeutic effects attributed to the drug could as readily be caused by other factors.1 It is possible that alcoholics who take disulfiram regularly may be more highly motivated for recovery and' thus be more likely to succeed. The fear of possible adverse physical reactions might itself curtail drinking, so administration of a placebo might exert similar restraint. Although this "placebo" effect of oral treatment with disulfiram has not been demonstrated, it also has not been ruled out; hence it remains a possible explanation. These warnings notwithstanding, disulfiram is now being implanted surgically to ensure that reluctant patients receive their medication regularly. This technique, has, perhaps unwittingly, shed light on the possible placebo effect of disulfiram treatment. Although comparisons between implant therapy and oral administration indicate that longer periods of abstinence from alcohol are associated with the implant procedure,2'3 there is evidence that this is not due to the disulfiram.44 Measurements of blood concentrations of disulfiram and exhaled breakdown products of the drug indicate that the surgical implant is relatively inert. Even intravenous infusions of alcohol in patients with im-
134 CMA JOURNAL/JANUARY 22, 1977/VOL. 116
FOR ANALGESIC ACTIVITY 0292* Tablets 0222*Tablets INDICATIONS: For relief of mild to moderate pain, fever and inflammation as in influenza, common cold, low back and neck pain, headache, trauma, following dental and surgical procedures. DOSAGE: 222.-Adults-1 or 2 tablets one to three times daily; Children's dosage, when recommended byaphysician:lOto 14 years, one tablet, one to three times daily; 5 to 10 years, one-half tablet, one to three times daily; 292*. Aduits-1 tablet two to three times daily. CONTRAINDICATIONS: Gastrointestinal ulceration and sensitivity to any of the components. WARNINGS: Salicylates increase the effects of anticoagulants. Caution Is necessary when salicylates and anticoagulants are prescribed concurrently. Also, salicylates may depress the concentration of prothrombin in the plasma. Large doses of salicylates may affect insulin requirements of diabetics. Salicylates may potentiate sulfonylurea hypoglycemic agents. Analgesic abuse (excessive and prolonged therapy) has been associated with nephropathy. TO AVOID ACCIDENTAL POISONING ACETYLSALICYLIC ACID PREPARATIONS MUST BE KEPT WELL OUT OF REACH OF CHILDREN. PRECAUTIONS: Give with caution to patients with asthma, other allergic conditions, bleeding tendencles, or hypoprothrombinemia. Salicylates can produce changes in thyroid function tests. Observe care in use of codeine, aithough tolerance and addiction are rare. Give codeine with caution to patients with severe respiratory depression. Its depressant effect may be enhanced by concurrent administration of sedatives and tranquilizers. ADVERSE REACTIONS: Acetylsallcyllc acid: Gastrointestinal: dyspepsia, heartburn, nausea, vomiting, diarrhea, gastrointestinal ulceration and bleeding. Ear reactions: tinnitus, hearing loss. Hematologic: anemia, leukopenia, thrombocytopenia, purpura. Dermatologic and Hypersensitivity: urticaria, angioedema, pruritus, various skin eruptions, asthma and anaphylaxis. Miscellaneous: mental confusion, drowsiness, sweating and thirst. Codalne: Average or large doses may cause various gastrointestinal symptoms such as nausea, vomiting and constipation. CaffeIne: May cause nausea, nervousness, insomnia, headache, vomiting, palpitation, vertigo, muscle tremor, sensory disturbances, excessive diuresis in sensitive patients. Large doses may cause gastric ulceration. FULL INFORMATION AVAILABLE ON REQUEST HOW SUPPLIED 0292k Tablets - Peach, 0 marked, scored, engraved 292 on one side. Each tablet contains: acetylsalicylic acid 375 mg, caffeine citrate 30 mg, codeine phosphate 30mg. Available in bottles of 50 and 500. 0222* Tablets - White, scored, engraved 222 on one side. Each tablet contains: acetylsalicylic acid 375 mg, caffeine citrate 30 mg, codeine phosphate 8 mg. Available in tubes of 12; botties of 40 and 100 also bottles of 60 with safety cap.
FOUNDED IN CANADA IN 1899 CHARLES E. PROEST A CO. KIRKLAND (MONTREAL) CANADA
8Trad.ark (MC-387a)
IRMACI
0.5mg.norethindrone 35mcg.ethinyl estradiol INDICATION: MODACON Tablets are indicated for conception control. ACTION: MODACON acts through the mechanism ot gonadotrophin suppression, i.e., through the estrogenic and progestational actions of the active ingredients. Alterations in cervical macno and in the endometrium may also contribate to the efficacy at MODACON. CONTRAINDICATIONS: 1. Thrombophlebitis, thromboembolic disorders, cerebral vascular disease, coronary thrombosis, or a history of these conditions. 2. Significant liver dysfunction or disease. 3. History of cholestatic jaundice. 4. Known orsuspected malignancyof the breast orgenitaltractorhistory of these conditions. 5. Known or suspected estrogen-dependent neoplasia. 6. Undiagnosed abnormal vaginal bleeding. 7. Known or suspected pregnancy. 8. During the period a mother is breast feeding an infant. g. Anyocularlesion associated with ophthalmicvascufardisease such us partial or complete loss of vision, defect in visual fields or diplopia. 10. Classical migraine. WARNINGS: 1. Discontinue medication at the earliest manifestations of: A. Thrembeembellc Oleerdera: (i)thrombophlebitis (ii) cerebrovascular disorders (including hemorrhage) (iii) pulmonary embolism (iv) myocardial luchemia (v) retinal thrombosis. B. VIsual DIsturbances: (i) gradual or sudden, partial or complete loss of vision (ii) proptosis or diplopia (iii) onset or aggravation of migraine (iv) papilledema (v) ophthalmic vascular lesions. C. Development of headache of a new pattern which is recurrent, persistent or severe and undiagnosed. D. Psychiatric disturbances. 2. Rule out pregnancy before initiating or continuing administration of oral contraceptives in patients who have missed two consecutive menstrual periods. If the patient has not adhered to the prescribed regimen, pregnancy should be cansidered at the time of the first missed menstrual period. 3. Patientuwith conditions such asepilepay, asthma, and cardiacor renal dysfunction which may be adversely affected by some degree at fluid retention require careful observation. 4. In women with underiying risk factors for coronary artery disease (such as hypertension, bypercholesterolemia, obesity, diabetes, history of pre-eclamptic tosemia), oral contraceptives have been reported as an additional rink factor. PRECAUTIONS: 1. PhysIcal esamlmatlem and follnw-ey A. Before oral contraceptives are prescribed, a thorough physical examination ahould be made including a blood pressure determination. Breasta, liverand pelvic organushould be examined, and a Papanicoluos smear ahould be taken. B. The first follow-up examination should be done within 6 months; thereaffer, examinations should be made at least once a year. At each annual visit, esamination should include those procedureu performed at the Initial visit. 2. Hepatlc functIon A. Patients with an history of jaundice should be prescribed oral contraceptlveswith great care and underclose observation. The development of severe generalized pruritus or icterus requires that the medication be withdrawn untllthe problem is resolved. If the jaundice should proveto be cholestatic in type, administration of oral contraceptives should not be resumed. B. Changes in composition of the bile and the appearance of cholesterol gall atones have been reported in patients taking oral contraceptives. C. Hepatic neoplasms (mostly adeesmas) and nodular hyperplasias or hamartomas have been reported in users of oral contraceptives. Although these tumoura are uncommon. they have caused fatal intra-abdominal hemorrhage and uhould be considered in women presenting with acute abdominal pain, an abdominal mass or evidence of intra-abdominal bleeding. 3. Hypertemalem Patients with essential hypertension may be prescribed oral contraceptives but only under close supervision. If a significant elevation of blood pressure in previously normotensive or hypertensive subjects occurs at any time during the administration of the drug, causation of medication in necessary. 4. DIabetes Diabetic patients orthose with a family history of diabetes ahoald be observed closely to detect any alterations in carbohydrate metabolism. Latent diabetica who can be kept under close supervision may be prescribed oral contraceptives. Young patients with overt diabeteuwbose disease is of recentorigin, well-controlled, and not associated with hypertension orothersignn of vasculardisease such as oculartundal changeu, ahould be closely observed. 5. MetabolIc med endocrIne ileemnen A. In metabolic or endocrine diseases, and when the metabolism of calcium and phosphorus is abnormal, careful clinical evaluation should precede medication and a regular follow-up is recommended. B. The risk of complications due to adrenocorticol insufficiency appears to be minimal with oral contraceptive therapy. However, physiciann abould be aware of this rare problem. C. Estrogen-progestogencombinatlOns maycaunean increase in plasma lipoproteinsand should beadministeredwith cautionto women knowoto have preexintent hyperlipoproteinemis. 6. Breasts Special judgment should be used in prescribing oral contraceptives to women with fibrocyntic disease of the breast. 7. VagInal bleedIng Persistent irregular vaginal bleeding requires investigatIon to exclude the possibility of pregnancy or neoplasm. If these can be excluded, appropriate adjustment of dosage may be indicated. S. Flbrolds Patients with fibroids (lelomyomata) should be carefully observed. Sudden enlargement, pain, ortendereess of uterine fibroids require discontinnance of medication. 8.Age A. Adolescent patients should be assessed for adeqeste skeletal development priorto medication which should be used with caution since oral contraceptives may accelerate epiphyseal closure. B. Dral contraceptive therapy may mask the onset of the climacteric. C. In women overthe age of 40 years, use of oral contraceptives may be associated with an increased risk of cardiovascular nod metabolic complications. Inthisagegroup, whenfertilitycontroliudesired, someotber non-hormonal method for contraception should be advised.
10 Emotional disorders Patients with a history at emotional disturbances, especially the depressive type, are more prone to have a recurrence at depression while taking oral contraceptives. In cases at serious recsrrence, the medication should he discontinued. 11. Laboratory tests Laboratory test results shoold not be considered reliable unless oral contraceptive therapy has been discontinoed tar two to tour months tar therapy may after the following determinations and possibly mash underlying disease: A. Liver function teats: Bromoslphalein retention - increased. SGOTvariously reported elevations from zero to sin or seven percent to sixteen to eighteen percent. Alkaline phosphalase - slightly elevated in two percent or less of patients. Serum bilirubin - elevations noted rarely or not at all. B. Coagulation tests: Elevation of test values reported for such parameters as prothrombin and Factors VII, VIII, IX and X. Increased platelet aggregability. Decreased antithrombin Ill. C. Thyroid function tests: Protein binding of thyroxine is increased as indicated by increased P81 and total serum thyroxine concentrations and decreased Ta resin uptake. 0. Adrenocortical function tests: Plasma cortisol is increased. Reported impaired adrenocorticol response to metyrapone administration is now attributed to accelerated metyrapone conjugation by estrogen. E. Reproductive endocrine profile changes: Luteinizing hormone - the mid-cycle surge is suppressed with variable effects on tonic levels being noted. Pregnanediol - suppressed. Urinary estrogens - slight or zero increase. F. Othertests: Phospholipidsandtri-glycerides - ocreased. Serum blase values - decreased. Tryptophon metabolism is disturbed. Increased glucose blood levels. 12. Tissuespeelmeos If surgical proceduresare performed, pathologists should be advised of oral contraceptive therapy when specimens are submitted for examination. 13. Return to fertility A. After discontinuing oral contraceptives, the patient should await the resumption of normal ovulatory cycles before attempting to became pregnant. 8. Women with a history of oligomenorrheaorsecondary amenorrhesor women with irregularcyctes may remain anovulatory or become amenorrheic following estrogen-progestogen combination therapy. 14. Fetal ahuormalitles Fetal sheormalities have been reported to occur nIbs offspring of women who havetaken progestogens and/orextrogens during pregnancy. The safetyof oral contraceptives in pregnancy has not been demonstrated. Pregnancy should be ruled out before initiating or continuing the contraceptive regimen. Pregnancy should always be considered if withdrawal bleeding dees not occur. 15. Thrembeembolic somplisatioms - pest eergery Retrospective studies have reported an increased risk of post surgery thrombeembolic complications in oralcontraceptive users. It has been recommeodedthat therapy be discontinued at least one month psorto elective surgery and not resumed until at leastuwo weeks after hospital discharge following surgery of the type associated with the increased risk of thromboembolism. 16. Coneemlfant medleatlee A reduced ethcacy and increase in incidence of breakthrough bleeding have been reported in oral contraceptive users treated concomitantly with barbiturates, rifampicin, phenylbutazone, phenytoin or ampicillin. ADVERSE REACTiONS: Side effects most commonly reported in early cycles of oral contraceptivetherapy include breakthrough bleeding, spotting, nausea, vomiting and other gastrointestinal disturbances, weight change. These frequently decrease with continued use. Other common side effects include: change in menstrual flow, edema, chlsasma (which may persist pest therapy), amenorrhea, breast changes (tenderness, enlargement and secretion). In additiontothe conditions and disorderadiscussed above, thefollowing have been reported as adverse reactions in patients using MODACON Tablets. Cystitis-like syndrome Neuro-vascular lesions of the eye Headache Rash Nervousnesa Cervical erosion and secretions Fatigue Suppression of lactation Hirsutism Pre-menstrual-like syndrome Loss of scalp hair Changes in libido Erythema multitorme Leg cramps Erythema nodosum Relative pyridoxine deficiency Itching Hemorrhagic eruptions Anovulation post-treatment Cholestatic jaundice Dizziness Mental depression Migraine The following adverse reactions have been observed in users of oral contraceptives: Hepatic neoplasm Thrombophlebitis Cholesterol gallstones Pulmonary embolism TREATMENT OF OVERDOSAGE OR ACCIDENTAL INGESTION: In case of overdosage or accidental ingestion by children, the physician should observe the patient closely although no medication is required. Gastric lavage should be given if considered necessary. DOSAGE AND ADMINISTRATION: AvillablIlty MODACON Tablets are available in 21-day and 28-day DIALPAK. Tablet Dispenser Units. Compesltlee Each white tablet engraved on both aides with Ortho 112' contains 0.50mg norethindrone and 0.035 mg ethinyl estradiol. In the 28-day regimen the green tablets contain inert ingredidots. 21-day Regimes: Forthefiralcycle only, haveyourpatienttake one white tablet a day for 21 days, starting on day Sal her menstrual cycle. At the end of thecourse of MODACON she stopsthetubletsforoneweek. From nowon, she simply completeseachcourse of tablets, stopping anthe end of each courseforoneweek. Thetablets should bestarted whetherornot menstruation has occurred or is finished. If spotting or bleeding should occur whiletaking MODACON, she should continue taking the tablets in the regular manner. 26-Day Regimes: Have your patient take one white tablet a day for three weeks starting oaths first Sunday utter her menstrual cycle begins. For example, if her period begins Monday to Saturday, she takes her first tablet the following Sunday. If herperiod begins on a Sunday, she takes herfirattabletthat very day. Shethentakesoneinert greentabletdailyfor oneweekin orderto maintain aregular28-day cycle. Withdrawal bleeding should occur during the week of taking the inert tablets. However, whether or not bleeding has occurred or is finished, the white tablets should be started again the day afterthe last green tablet is taken. Duratio, of Uae: The 21-day or 28-day cyclic therapy may be continued for as long as conception control is desired. Reference: 1. Data on File, Ortho Pharmaceutical (Canada) Ltd.
OR.HO PHARMACEUliCAL (CAt.tADA. LiD-DON MIU&ONTARIO Trademark
138 CMA JOURNAL/JANUARY 22, 1977/VOL. 116
© Ortho 1876
plants have failed to produce the disulfiram-alcohol challenge reaction. In addition, reports of patients who consume alcohol while the implant is thought to be active reveal that only a small percentage experience any reaction, and this reaction is atypical and more akin to anxiety. Waclawik7 stated that "several sham implants... gave the same result as the real ones". it seems that the "active" preparation is a placebo. Although some workers may disagree with this conclusion,8 careful investigations have found "no demonstrable evidence that the success of implantation is associated with the pharmacological effect of disulfiram" .6 Judging from the increasing interest in and use of the surgical implant technique, the conclusion that disulfiram implantation acts as a psychological rather than a pharmacologic deterrent appears not to have received the serious consideration it deserves. Subjecting patients to potentially hazardous medication and surgical risks can hardly be justified until the placebo effect of disulfiram treatment is adequately assessed and ruled out. ROBERT MANN, BA M. VOGEL-SPROTr, PH 0 Department of psychology University of Waterloo Waterloo, Ont.
References 1. MorriN 3: Drug-induced attenuation of alcohol consumption. Q I Stud Alcohol 34: 444, 1973 2. MALCOLM M, MADDEN 3: Use of disulfiram implantation in alcoholism. Br I Psychiatry 123: 41, 1973 3. WHYm C, O'BRIEN P: Disulfiram implant: a controlled trial. Br I Psychiatry 124: 42, 1974 4. MALCOLM M, MADDEN 3, WILLIAMS A: Disulfiram implantation critically evaluated. Br I Psychiatry 125: 485, 1974 5. OaEEHOLZER A: Follow-up study of nineteen alcoholic patients treated by means of tetraethylthiuram disulphide (Antabuse) implants. Br I Addict 69. 19 1974 6. LEWIS M, BLAND k, BAILE W: Disulfirani implantation for alcoholism. Can Psychiatr Assoc 1 20: 283, 1975 7. WACLAWIK P: Esperal treatment of alcoholism in the general hospital (abstr). Q I Stud Alcohol 33: 250, 1972 8. WILSON A, DAvIDSoN W, WHiTE 3: Disulfiram-ethanol reaction to implanted disulfiram. Can Psychlatr Assoc 1 21: 217, 1976
Tartrazine-containing drugs To the editor: Two additional corrections are required to the list of drugs published in the article "Tartrazinecontaining drugs" (Can Med Assoc J 115: 332, 1976) by Dr. W.R. Bartle. Mytelase, 10 mg does not contain tartrazine; however, Mytelase, 25 mg does. Similarly, Talwin tablets, 50 mg do not contain tartrazine but Talwin Coinpound-25 does. W. WASSENAAR, MD, M SC Medical director Winthrop Laboratories Aurora, Out.
To the editor: Dr. Newman has sug gested that the authors of the collabo rative study of prenatal diagnosis 01 genetic disease are pressing for al mothers over 35 years of age to hav prenatal diagnosis as a "make-work' project. I am sure that all of us wh were involved in the study had n such thing in mind and in fact hav been stretched to the limit of our re sources to try to meet the demand frori the women themselves. A small per centage of pregnant women over 3. years of age (about 1 to 15% depend ing on the province) (Fig. 1 in the col laborative study) shows that the de mand has been increasing sharply. Dr. Newman also suggests that w. should be advising against pregnanc. rather than "killing" the abnorma fetuses. None of us "advise" eithe prenatal diagnosis or therapeutic abor tion; we attempt to inform the familie: of their risks and available options an help them make a decision in the ligh of their perception of the burden 0: the disease in question, the degree o' their desire to have more children am their religious or ethical beliefs. Thi data from the collaborative stud' show that only 5% of the pregnancie: of women who underwent amniocen tesis for prenatal diagnosis were selec tively aborted, that the proceduri served as reassurance for the parent: of the fetus, and that in some case; amniocentesis may have prevente( ha.uitw
ii..rfrwmpe
because of fear that the fetus was defective, when the fetus was in fact normal. Only 3% of all women undergoing prenatal diagnosis do so because of biochemical disease - those Dr. Newman suggests may increase the number of carriers in the population. Furthermore, each biochemical disease is extremely rare and the possible slight increase in gene frequencies for these diseases will not substantially increase the number of homozygotes. It is understandable that the main aim of doctors is to attempt to cure or at least improve the health of their patients, as Dr. Newman states. It is surely also important that doctors attempt to prevent disease; this, in the instances of our patients (the parents), will alleviate a great deal of suffering. NANCY E. SIMPSON, PH D, FCCMG Professor and chairman Division of medical genetics Department of pediatrics Queen's University Kingston, Ont.
Antabuse implants: placebo treatment for alcoholism? To the editor: Since the introduction of disulfiram (Antabuse) in 1948, routine use of this agent in the treatment of alcoholism has become widespread. Although there are numerous reports on the beneficial effects of its oral administration, careful reviews of this literature reveal that the therapeutic effects attributed to the drug could as readily be caused by other factors.1 It is possible that alcoholics who take disulfiram regularly may be more highly motivated for recovery and' thus be more likely to succeed. The fear of possible adverse physical reactions might itself curtail drinking, so administration of a placebo might exert similar restraint. Although this "placebo" effect of oral treatment with disulfiram has not been demonstrated, it also has not been ruled out; hence it remains a possible explanation. These warnings notwithstanding, disulfiram is now being implanted surgically to ensure that reluctant patients receive their medication regularly. This technique, has, perhaps unwittingly, shed light on the possible placebo effect of disulfiram treatment. Although comparisons between implant therapy and oral administration indicate that longer periods of abstinence from alcohol are associated with the implant procedure,2'3 there is evidence that this is not due to the disulfiram.44 Measurements of blood concentrations of disulfiram and exhaled breakdown products of the drug indicate that the surgical implant is relatively inert. Even intravenous infusions of alcohol in patients with im-
134 CMA JOURNAL/JANUARY 22, 1977/VOL. 116
FOR ANALGESIC ACTIVITY 0292* Tablets 0222*Tablets INDICATIONS: For relief of mild to moderate pain, fever and inflammation as in influenza, common cold, low back and neck pain, headache, trauma, following dental and surgical procedures. DOSAGE: 222.-Adults-1 or 2 tablets one to three times daily; Children's dosage, when recommended byaphysician:lOto 14 years, one tablet, one to three times daily; 5 to 10 years, one-half tablet, one to three times daily; 292*. Aduits-1 tablet two to three times daily. CONTRAINDICATIONS: Gastrointestinal ulceration and sensitivity to any of the components. WARNINGS: Salicylates increase the effects of anticoagulants. Caution Is necessary when salicylates and anticoagulants are prescribed concurrently. Also, salicylates may depress the concentration of prothrombin in the plasma. Large doses of salicylates may affect insulin requirements of diabetics. Salicylates may potentiate sulfonylurea hypoglycemic agents. Analgesic abuse (excessive and prolonged therapy) has been associated with nephropathy. TO AVOID ACCIDENTAL POISONING ACETYLSALICYLIC ACID PREPARATIONS MUST BE KEPT WELL OUT OF REACH OF CHILDREN. PRECAUTIONS: Give with caution to patients with asthma, other allergic conditions, bleeding tendencles, or hypoprothrombinemia. Salicylates can produce changes in thyroid function tests. Observe care in use of codeine, aithough tolerance and addiction are rare. Give codeine with caution to patients with severe respiratory depression. Its depressant effect may be enhanced by concurrent administration of sedatives and tranquilizers. ADVERSE REACTIONS: Acetylsallcyllc acid: Gastrointestinal: dyspepsia, heartburn, nausea, vomiting, diarrhea, gastrointestinal ulceration and bleeding. Ear reactions: tinnitus, hearing loss. Hematologic: anemia, leukopenia, thrombocytopenia, purpura. Dermatologic and Hypersensitivity: urticaria, angioedema, pruritus, various skin eruptions, asthma and anaphylaxis. Miscellaneous: mental confusion, drowsiness, sweating and thirst. Codalne: Average or large doses may cause various gastrointestinal symptoms such as nausea, vomiting and constipation. CaffeIne: May cause nausea, nervousness, insomnia, headache, vomiting, palpitation, vertigo, muscle tremor, sensory disturbances, excessive diuresis in sensitive patients. Large doses may cause gastric ulceration. FULL INFORMATION AVAILABLE ON REQUEST HOW SUPPLIED 0292k Tablets - Peach, 0 marked, scored, engraved 292 on one side. Each tablet contains: acetylsalicylic acid 375 mg, caffeine citrate 30 mg, codeine phosphate 30mg. Available in bottles of 50 and 500. 0222* Tablets - White, scored, engraved 222 on one side. Each tablet contains: acetylsalicylic acid 375 mg, caffeine citrate 30 mg, codeine phosphate 8 mg. Available in tubes of 12; botties of 40 and 100 also bottles of 60 with safety cap.
FOUNDED IN CANADA IN 1899 CHARLES E. PROEST A CO. KIRKLAND (MONTREAL) CANADA
8Trad.ark (MC-387a)
IRMACI
0.5mg.norethindrone 35mcg.ethinyl estradiol INDICATION: MODACON Tablets are indicated for conception control. ACTION: MODACON acts through the mechanism ot gonadotrophin suppression, i.e., through the estrogenic and progestational actions of the active ingredients. Alterations in cervical macno and in the endometrium may also contribate to the efficacy at MODACON. CONTRAINDICATIONS: 1. Thrombophlebitis, thromboembolic disorders, cerebral vascular disease, coronary thrombosis, or a history of these conditions. 2. Significant liver dysfunction or disease. 3. History of cholestatic jaundice. 4. Known orsuspected malignancyof the breast orgenitaltractorhistory of these conditions. 5. Known or suspected estrogen-dependent neoplasia. 6. Undiagnosed abnormal vaginal bleeding. 7. Known or suspected pregnancy. 8. During the period a mother is breast feeding an infant. g. Anyocularlesion associated with ophthalmicvascufardisease such us partial or complete loss of vision, defect in visual fields or diplopia. 10. Classical migraine. WARNINGS: 1. Discontinue medication at the earliest manifestations of: A. Thrembeembellc Oleerdera: (i)thrombophlebitis (ii) cerebrovascular disorders (including hemorrhage) (iii) pulmonary embolism (iv) myocardial luchemia (v) retinal thrombosis. B. VIsual DIsturbances: (i) gradual or sudden, partial or complete loss of vision (ii) proptosis or diplopia (iii) onset or aggravation of migraine (iv) papilledema (v) ophthalmic vascular lesions. C. Development of headache of a new pattern which is recurrent, persistent or severe and undiagnosed. D. Psychiatric disturbances. 2. Rule out pregnancy before initiating or continuing administration of oral contraceptives in patients who have missed two consecutive menstrual periods. If the patient has not adhered to the prescribed regimen, pregnancy should be cansidered at the time of the first missed menstrual period. 3. Patientuwith conditions such asepilepay, asthma, and cardiacor renal dysfunction which may be adversely affected by some degree at fluid retention require careful observation. 4. In women with underiying risk factors for coronary artery disease (such as hypertension, bypercholesterolemia, obesity, diabetes, history of pre-eclamptic tosemia), oral contraceptives have been reported as an additional rink factor. PRECAUTIONS: 1. PhysIcal esamlmatlem and follnw-ey A. Before oral contraceptives are prescribed, a thorough physical examination ahould be made including a blood pressure determination. Breasta, liverand pelvic organushould be examined, and a Papanicoluos smear ahould be taken. B. The first follow-up examination should be done within 6 months; thereaffer, examinations should be made at least once a year. At each annual visit, esamination should include those procedureu performed at the Initial visit. 2. Hepatlc functIon A. Patients with an history of jaundice should be prescribed oral contraceptlveswith great care and underclose observation. The development of severe generalized pruritus or icterus requires that the medication be withdrawn untllthe problem is resolved. If the jaundice should proveto be cholestatic in type, administration of oral contraceptives should not be resumed. B. Changes in composition of the bile and the appearance of cholesterol gall atones have been reported in patients taking oral contraceptives. C. Hepatic neoplasms (mostly adeesmas) and nodular hyperplasias or hamartomas have been reported in users of oral contraceptives. Although these tumoura are uncommon. they have caused fatal intra-abdominal hemorrhage and uhould be considered in women presenting with acute abdominal pain, an abdominal mass or evidence of intra-abdominal bleeding. 3. Hypertemalem Patients with essential hypertension may be prescribed oral contraceptives but only under close supervision. If a significant elevation of blood pressure in previously normotensive or hypertensive subjects occurs at any time during the administration of the drug, causation of medication in necessary. 4. DIabetes Diabetic patients orthose with a family history of diabetes ahoald be observed closely to detect any alterations in carbohydrate metabolism. Latent diabetica who can be kept under close supervision may be prescribed oral contraceptives. Young patients with overt diabeteuwbose disease is of recentorigin, well-controlled, and not associated with hypertension orothersignn of vasculardisease such as oculartundal changeu, ahould be closely observed. 5. MetabolIc med endocrIne ileemnen A. In metabolic or endocrine diseases, and when the metabolism of calcium and phosphorus is abnormal, careful clinical evaluation should precede medication and a regular follow-up is recommended. B. The risk of complications due to adrenocorticol insufficiency appears to be minimal with oral contraceptive therapy. However, physiciann abould be aware of this rare problem. C. Estrogen-progestogencombinatlOns maycaunean increase in plasma lipoproteinsand should beadministeredwith cautionto women knowoto have preexintent hyperlipoproteinemis. 6. Breasts Special judgment should be used in prescribing oral contraceptives to women with fibrocyntic disease of the breast. 7. VagInal bleedIng Persistent irregular vaginal bleeding requires investigatIon to exclude the possibility of pregnancy or neoplasm. If these can be excluded, appropriate adjustment of dosage may be indicated. S. Flbrolds Patients with fibroids (lelomyomata) should be carefully observed. Sudden enlargement, pain, ortendereess of uterine fibroids require discontinnance of medication. 8.Age A. Adolescent patients should be assessed for adeqeste skeletal development priorto medication which should be used with caution since oral contraceptives may accelerate epiphyseal closure. B. Dral contraceptive therapy may mask the onset of the climacteric. C. In women overthe age of 40 years, use of oral contraceptives may be associated with an increased risk of cardiovascular nod metabolic complications. Inthisagegroup, whenfertilitycontroliudesired, someotber non-hormonal method for contraception should be advised.
10 Emotional disorders Patients with a history at emotional disturbances, especially the depressive type, are more prone to have a recurrence at depression while taking oral contraceptives. In cases at serious recsrrence, the medication should he discontinued. 11. Laboratory tests Laboratory test results shoold not be considered reliable unless oral contraceptive therapy has been discontinoed tar two to tour months tar therapy may after the following determinations and possibly mash underlying disease: A. Liver function teats: Bromoslphalein retention - increased. SGOTvariously reported elevations from zero to sin or seven percent to sixteen to eighteen percent. Alkaline phosphalase - slightly elevated in two percent or less of patients. Serum bilirubin - elevations noted rarely or not at all. B. Coagulation tests: Elevation of test values reported for such parameters as prothrombin and Factors VII, VIII, IX and X. Increased platelet aggregability. Decreased antithrombin Ill. C. Thyroid function tests: Protein binding of thyroxine is increased as indicated by increased P81 and total serum thyroxine concentrations and decreased Ta resin uptake. 0. Adrenocortical function tests: Plasma cortisol is increased. Reported impaired adrenocorticol response to metyrapone administration is now attributed to accelerated metyrapone conjugation by estrogen. E. Reproductive endocrine profile changes: Luteinizing hormone - the mid-cycle surge is suppressed with variable effects on tonic levels being noted. Pregnanediol - suppressed. Urinary estrogens - slight or zero increase. F. Othertests: Phospholipidsandtri-glycerides - ocreased. Serum blase values - decreased. Tryptophon metabolism is disturbed. Increased glucose blood levels. 12. Tissuespeelmeos If surgical proceduresare performed, pathologists should be advised of oral contraceptive therapy when specimens are submitted for examination. 13. Return to fertility A. After discontinuing oral contraceptives, the patient should await the resumption of normal ovulatory cycles before attempting to became pregnant. 8. Women with a history of oligomenorrheaorsecondary amenorrhesor women with irregularcyctes may remain anovulatory or become amenorrheic following estrogen-progestogen combination therapy. 14. Fetal ahuormalitles Fetal sheormalities have been reported to occur nIbs offspring of women who havetaken progestogens and/orextrogens during pregnancy. The safetyof oral contraceptives in pregnancy has not been demonstrated. Pregnancy should be ruled out before initiating or continuing the contraceptive regimen. Pregnancy should always be considered if withdrawal bleeding dees not occur. 15. Thrembeembolic somplisatioms - pest eergery Retrospective studies have reported an increased risk of post surgery thrombeembolic complications in oralcontraceptive users. It has been recommeodedthat therapy be discontinued at least one month psorto elective surgery and not resumed until at leastuwo weeks after hospital discharge following surgery of the type associated with the increased risk of thromboembolism. 16. Coneemlfant medleatlee A reduced ethcacy and increase in incidence of breakthrough bleeding have been reported in oral contraceptive users treated concomitantly with barbiturates, rifampicin, phenylbutazone, phenytoin or ampicillin. ADVERSE REACTiONS: Side effects most commonly reported in early cycles of oral contraceptivetherapy include breakthrough bleeding, spotting, nausea, vomiting and other gastrointestinal disturbances, weight change. These frequently decrease with continued use. Other common side effects include: change in menstrual flow, edema, chlsasma (which may persist pest therapy), amenorrhea, breast changes (tenderness, enlargement and secretion). In additiontothe conditions and disorderadiscussed above, thefollowing have been reported as adverse reactions in patients using MODACON Tablets. Cystitis-like syndrome Neuro-vascular lesions of the eye Headache Rash Nervousnesa Cervical erosion and secretions Fatigue Suppression of lactation Hirsutism Pre-menstrual-like syndrome Loss of scalp hair Changes in libido Erythema multitorme Leg cramps Erythema nodosum Relative pyridoxine deficiency Itching Hemorrhagic eruptions Anovulation post-treatment Cholestatic jaundice Dizziness Mental depression Migraine The following adverse reactions have been observed in users of oral contraceptives: Hepatic neoplasm Thrombophlebitis Cholesterol gallstones Pulmonary embolism TREATMENT OF OVERDOSAGE OR ACCIDENTAL INGESTION: In case of overdosage or accidental ingestion by children, the physician should observe the patient closely although no medication is required. Gastric lavage should be given if considered necessary. DOSAGE AND ADMINISTRATION: AvillablIlty MODACON Tablets are available in 21-day and 28-day DIALPAK. Tablet Dispenser Units. Compesltlee Each white tablet engraved on both aides with Ortho 112' contains 0.50mg norethindrone and 0.035 mg ethinyl estradiol. In the 28-day regimen the green tablets contain inert ingredidots. 21-day Regimes: Forthefiralcycle only, haveyourpatienttake one white tablet a day for 21 days, starting on day Sal her menstrual cycle. At the end of thecourse of MODACON she stopsthetubletsforoneweek. From nowon, she simply completeseachcourse of tablets, stopping anthe end of each courseforoneweek. Thetablets should bestarted whetherornot menstruation has occurred or is finished. If spotting or bleeding should occur whiletaking MODACON, she should continue taking the tablets in the regular manner. 26-Day Regimes: Have your patient take one white tablet a day for three weeks starting oaths first Sunday utter her menstrual cycle begins. For example, if her period begins Monday to Saturday, she takes her first tablet the following Sunday. If herperiod begins on a Sunday, she takes herfirattabletthat very day. Shethentakesoneinert greentabletdailyfor oneweekin orderto maintain aregular28-day cycle. Withdrawal bleeding should occur during the week of taking the inert tablets. However, whether or not bleeding has occurred or is finished, the white tablets should be started again the day afterthe last green tablet is taken. Duratio, of Uae: The 21-day or 28-day cyclic therapy may be continued for as long as conception control is desired. Reference: 1. Data on File, Ortho Pharmaceutical (Canada) Ltd.
OR.HO PHARMACEUliCAL (CAt.tADA. LiD-DON MIU&ONTARIO Trademark
138 CMA JOURNAL/JANUARY 22, 1977/VOL. 116
© Ortho 1876
plants have failed to produce the disulfiram-alcohol challenge reaction. In addition, reports of patients who consume alcohol while the implant is thought to be active reveal that only a small percentage experience any reaction, and this reaction is atypical and more akin to anxiety. Waclawik7 stated that "several sham implants... gave the same result as the real ones". it seems that the "active" preparation is a placebo. Although some workers may disagree with this conclusion,8 careful investigations have found "no demonstrable evidence that the success of implantation is associated with the pharmacological effect of disulfiram" .6 Judging from the increasing interest in and use of the surgical implant technique, the conclusion that disulfiram implantation acts as a psychological rather than a pharmacologic deterrent appears not to have received the serious consideration it deserves. Subjecting patients to potentially hazardous medication and surgical risks can hardly be justified until the placebo effect of disulfiram treatment is adequately assessed and ruled out. ROBERT MANN, BA M. VOGEL-SPROTr, PH 0 Department of psychology University of Waterloo Waterloo, Ont.
References 1. MorriN 3: Drug-induced attenuation of alcohol consumption. Q I Stud Alcohol 34: 444, 1973 2. MALCOLM M, MADDEN 3: Use of disulfiram implantation in alcoholism. Br I Psychiatry 123: 41, 1973 3. WHYm C, O'BRIEN P: Disulfiram implant: a controlled trial. Br I Psychiatry 124: 42, 1974 4. MALCOLM M, MADDEN 3, WILLIAMS A: Disulfiram implantation critically evaluated. Br I Psychiatry 125: 485, 1974 5. OaEEHOLZER A: Follow-up study of nineteen alcoholic patients treated by means of tetraethylthiuram disulphide (Antabuse) implants. Br I Addict 69. 19 1974 6. LEWIS M, BLAND k, BAILE W: Disulfirani implantation for alcoholism. Can Psychiatr Assoc 1 20: 283, 1975 7. WACLAWIK P: Esperal treatment of alcoholism in the general hospital (abstr). Q I Stud Alcohol 33: 250, 1972 8. WILSON A, DAvIDSoN W, WHiTE 3: Disulfiram-ethanol reaction to implanted disulfiram. Can Psychlatr Assoc 1 21: 217, 1976
Tartrazine-containing drugs To the editor: Two additional corrections are required to the list of drugs published in the article "Tartrazinecontaining drugs" (Can Med Assoc J 115: 332, 1976) by Dr. W.R. Bartle. Mytelase, 10 mg does not contain tartrazine; however, Mytelase, 25 mg does. Similarly, Talwin tablets, 50 mg do not contain tartrazine but Talwin Coinpound-25 does. W. WASSENAAR, MD, M SC Medical director Winthrop Laboratories Aurora, Out.
