IN EPILEPSY, ADD I Frisium 10 mg (clobazam) TO ACHIEVE SEIZURE CONTROL KING MEDICAL Frisium (clobazam) Tablets 10 mg. therapy with Frisium is indicated, blood counts and liver function THERAPEUTIC CLASSIFICATION Anticonvulsant for adjunctive should be monitored periodically. Use in Patients with Acute, Severe therapy. INDICATIONS Frisium (clobazam) has been found to be of Respiratory Insufficiency: In patients with acute, severe respiratory THE CANADIAN value as adjunctive therapy in patients with epilepsy who are not insufficiency, respiratory function should be monitored. Laboratory adequately stabilized with their current anti-convulsant therapy. Tests: If Frisium is administered for repeated cycles of therapy, CONTRAINDICATIONS Hypersensitivity to clobazam, severe muscle periodic blood counts and liver and thyroid function tests are ELECTRODE PLACE weakness (myasthenia gravis) and narrow angle glaucoma. advisable. Drug Interactions: Most studies of the potential WARNINGS Use in the elderly: Frisium (clobazam) should be used interactions of clobazam with other anti-epileptic agents have failed to with caution in elderly and debilitated patients, and those with organic demonstrate significant interactions with phenytoin, phenobarbital, or • CHALGREN brain disorders, with treatment initiated at the lowest possible dose. carbamazepine. However, one study noted that the addition of [See Precautions!. Potentiation of drug effects: Patients should be clobazam caused a 25% increase in serum drug levels in 29% of cautioned about the possibility of additive effects when Frisium is patients taking carbamazepine, 63% of patients taking phenytoin, • DANTEC combined with alcohol or other drugs with central nervous system 13% of those taking valproate and 14% of those on phenobarbital. depressant effects. Patients should be advised against consumption The contradictory findings in different studies are presumably due to • KING MEDICAL of alcohol during treatment with Frisium. [See Precautions]. Physical variations in patient susceptibility, and although clinically significant and psychological dependence: Physical and psychological interactions are unusual, they may occur. Alcohol may also • MEDICOTEST dependence are known to occur in persons taking benzodiazepines. significantly increase plasma clobazam levels. Several of the Caution must be exercised if it is at all necessary to administer established anti-epileptic agents: carbamazepine, • PARKER LAB. Frisium to individuals with a history of drug misuse or those who may diphenylhydantoin, phenobarbital, valproic acid, cause the blood increase the dose on their own initiative. Such patients must be levels of clobazam to decrease slightly. Findings are less consistent • UNI-PATCH/CLASSIC placed under careful surveillance. Signs and symptoms ot withdrawal with regard to N-desmethylclobazam: serum levels are lower with may follow discontinuation of use of Frisium; thus it should not be concurrent valproic acid, but higher with carbamazepine and • D.O.WEAVER abruptly discontinued after prolonged use. [See Precautions). Use in diphenylhydantoin. Toxicologic Studies: In mouse, clobazam was pregnancy: Frisium should not be used in the first trimester of associated with hepatomas in high-dose males. In rat, an increased pregnancy and thereafter only if strictly indicated. Nursing mothers in incidence of thyroid adenomas was seen in males. There were three Please contact us for whom therapy with Frisium is indicated should cease breast-feeding, malignancies: two (male and female) in the thyroid and one (female) since clobazam passes into breast milk. Several studies have in the liver. The relevance ot these findings to man has not been Catalogues and Price List suggested an increased risk of congenital malformations associated established. ADVERSE REACTIONS From 19 published studies of with the use of minor tranquilizers (chlordiazepoxide, diazepam and Frisium (clobazam) use in epileptic patients, the overall incidence of meprobamate) during the first trimester of pregnancy. I) Frisium is side-effects was 33% of which drowsiness, dizziness and fatigue Tel: (905)833-3545 prescribed to a woman of child-bearing potential she should be were most frequently reported. Canadian experience provides a warned to consult her physician regarding the discontinuation of the similar overall incidence (32%) with drowsiness reported in 17.3% of drug if she intends to become, or suspects she might be, pregnant. patients, and 12% of patients terminating treatment because of side- Fax: (905) 833-3543 Anterograde amnesia: Anterograde amnesia is known to occur after effects. The incidence of side-effects was lower in patients under 16 administration of benzodiazepines. Use in patients with depression years of age (23.7%) than the incidence in adults (43.1%): p < 0.05, or psychosis: Frisium is not recommended for use in patients with whereas treatment discontinuation incidences were similar across age 145 Kingsworth Road depressive disorders or psychosis. PRECAUTIONS Driving and groups: 10.6% and 13.8% respectively. The following side-effects Hazardous Activities: Frisium (clobazam) possesses a mild central occurred at incidences of greater than 1% (ataxia (3.9%), weight gain King City • Ontario L7B 1K1 nervous system depressant effect, therefore patients should be [2.2%], dizziness [1.8%], nervousness [1.6%], behaviour disorder cautioned against driving, operating dangerous machinery or [1.4%], hostility and blurred vision [1.3%]) while other effects engaging in other hazardous activities, particularly in the dose occurred at a less than 1% incidence. Symptoms of tiredness may adjustment period, or until it has been established that they do not sometimes appear, especially at the beginning of treatment with become drowsy or dizzy. Use in the Elderly: Elderly and debilitated Frisium and when higher doses are used. Also in rare instances and patients, or those with organic brain syndrome, have been found to usually only temporarily, the patient may experience dryness of the be prone to the CNS depressant activity ot benzodiazepines even after mouth, constipation, loss of appetite, nausea, dizziness, muscle low doses. Manifestations of this CNS depressant activity include weakness, disorientation, tiredness, or a fine tremor of the fingers, ataxia, oversedation and hypotension. Therefore, medication should but also paradoxical reactions, e.g., restlessness and irritability. After be administered with caution to these patients, particularly if a drop in prolonged use of benzodiazepines, impairment of consciousness blood pressure might lead to cardiac complications. Initial doses combined with respiratory disorders has been reported in very rare should be low and increments should be made gradually, depending cases, particularly in elderly patients; it sometimes persisted for some on the response of the patient, in order to avoid oversedation, length of time. Under experimental conditions, impairment of Copies of articles neurological impairment and other possible adverse reactions. alertness has been observed to be less pronounced after therapeutic Dependence Liability: Frisium should not be administered to doses of clobazam than after other benzodiazepines. Nevertheless, individuals prone to drug abuse. Caution should be observed in all even when used as directed, the drug may alter reactivity to such an from this publication patients who are considered to have potential for psychological extent as to impair driving performance or the ability to operate dependence. Withdrawal symptoms have been observed after abrupt machinery, especially when it is taken in conjunction with alcohol. As discontinuation of benzodiazepines. These include irritability, with other drugs of this type (benzodiazepines), the therapeutic are now available nervousness, insomnia, agitation, tremors, convulsions, diarrhea, benefit must be balanced against the risk of habituation and abdominal cramps, vomiting and mental impairment. As with other dependence during prolonged use. Isolated cases of skin reactions from the UMI Article benzodiazepines, Frisium should be withdrawn gradually. Tolerance: such as rashes or urticaria have been observed. DOSAGE AND Loss of part or all of the anti-convulsant effectiveness of clobazam ADMINISTRATION As with other benzodiazepines, the possibility of a has been described in patients who have been receiving the drug for decrease in anticonvulsant efficacy in the course of treatment must be Clearinghouse. some time. There is no absolute or universal definition for the borne in mind. In patients with impaired liver and kidney function, phenomenon and reports vary widely on its development. The Frisium (clobazam) should be used in reduced dosage. Adults: Small reported success of clobazam in intermittent therapy in catamenial doses, 5-15 mg/day, should be used initially, gradually increasing to epilepsy implies that tolerance may be minimized by intermittent a maximum daily dose of 80 mg as necessary. Children: In infants Yes! I would like to know more about UMI Article Clear­ treatment but long-term follow-up is unreported. No studies have (< 2 years), the initial daily dose is 0.5-1 mg/kg/day. The initial dose inghouse. I am interested in electronic identified or predicted which patients are likely to develop tolerance or in children (2-16 years) should be 5 mg/day, which may be increased ordering through the following systemls): precisely when this might occur. Use in Mental and Emotional at 5-day intervals to a maximum of 40 mg/day. As with all D DIALOC/Dialorder Q ITT Dialcom Disorders: It should be recognized that suicidal tendencies may be benzodiazepines, abrupt withdrawal may precipitate seizures. It is D OnTyme D OCLC ILL Subsystem present in patients with emotional disorders; particularly those therefore recommended that Frisium be gradually reduced in dose depressed. Protective measures and appropriate treatment may be before treatment is discontinued. Administration: If the daily dose is D Other (please specify)- necessary and should be instituted without delay. Since excitement divided, the higher portion should be taken at night. Daily doses up to OI am interested in sending my order by mail. and other paradoxical reactions can result from the use of 30 mg may be taken as a single dose at night. AVAILABILITY Frisium D Please send me your current catalog and user instruc­ benzodiazepines in psychotic patients, Clobazam should not be used is available as white, uncoated, bevelled, round tablets of 7 mm tions for the system(s) 1 checked above. in patients suspected of having psychotic tendencies. Use in Patients diameter, marked with 'BGL' above and oelow the scorebreak on the with Impaired Renal or Hepatic Function: Clobazam requires obverse and the Hoechst 'Tower and Bridge' logo on the reverse. Name- dealkylation and hydroxylation before conjugation. Usual precautions Frisium 10 mg tablets are packaged in blisters of PVC film and Title— should be taken if Frisium is used in patients who may have some aluminium foil and are distributed in packs of 30 [3x10] tablets. impairment of renal or hepatic function. It is suggested that the dose Product Monograph available on request. Institution/Company- in such cases be carefully titrated. In patients for whom prolonged Department

Address City _Zip_ Reference: 1. Clobazam in the Treatment of Refractory Epilepsy - The Canadian Experience. A Retrospective Study, Canadian Clobazam Cooperative Group: Epilepsia, 1990;1-10.

FRI 2698/9053E See pages ibc, iii PAAB ouse 3, Hoechst and ®, Reg. Trademarks of Hoechst AG, Germany Hoechst Canada Inc., Montreal H4R 2E8 Hoechst Mail to: University Microfilms International 300 North Zeeb Road. Box 91 Ann Arbor, Ml 48106

Downloaded from https://www.cambridge.org/core. IP address: 170.106.35.234, on 27 Sep 2021 at 06:25:02, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0317167100040403 82 HEAD OF NEUROSURGERY PEDIATRIC NEUROLOGIST The Department of Surgery, Faculty of Medicine, University of Manitoba is search­ The University of Alberta, Department of Pediatrics, and the ing for a contingent geographical full-time Head of the Section of Neurosurgery Children's Health Centre of Northern Alberta is seeking a third full- effective January 1,1995. The responsibilities include the coordination of clinical time academic Pediatric Neurologist at the Assistant Professor level services between two major teaching Hospitals, the Health Sciences Centre and (salary range $39,230 - $55,526). Duties will include covering a busy the St. Boniface General Hospital as well as recruitment, organization, and super­ clinical service with two other full-time Pediatric Neurologists as well vision of undergraduate medical education and postgraduate training. The incum­ as major involvement in the teaching of medical students, residents, bent shall foster research initiatives and candidates should have an established and fellows. In addition, the ability to engage in independent clinical reputation of clinical experience and research accomplishments. or basic research in the neurosciences is expected.

Candidates must have Senior Specialty qualifications in Neurosurgery in the coun­ The candidate must be an MD eligible for Alberta Licensure and try of current practice and must be eligible for registration with the College of hold a Fellowship of the Royal College of Physicians and Surgeons of Physicians and Surgeons of Manitoba. Eligibility for, or certification in, Canada in Neurology (Pediatric Neurology). The candidate should Neurosurgery by the Royal College of Physicians and Surgeons of Canada is pre­ have a proven record of academic excellence in the Pediatric ferred. Specific requirements include the following: Substantial record of acade­ Neurosciences and subspecialty fellowship training would be an mic achievement in Neurosurgery with extensive experience in teaching and asset. research; Proven administrative experience in an academic environment; In accordance with Canadian immigration requirements, this adver­ Demonstrated constructive skills in interpersonal relations and communication. tisement is directed to Canadian citizens and permanent residents. Renumeration and academic rank will be commensurate with experience and Please reply in writing, including a Curriculum Vitae and three ref­ qualifications. erences to: The University of Manitoba encourages applications from qualified women and Dr. P.M. Olley men, including members of visible minorities. Aboriginal people, and persons with Professor and Chairman disabilities. The University provides a smoke-free work environment, save for spe­ Department of Pediatrics cially designated areas. Priority consideration will be given to Canadian citizens 2C3.67 Walter Mackenzie Centre and permanent residents. Interested candidates should apply, enclosing a curricu­ University of Alberta lum vitae in writing to: Edmonton, Alberta T6G 2R7 Dr. R.J.W. Blanchard, Professor and Head Department of Surgery, Health Sciences Centre Deadline for apphcations: March 15,1995. GC411-820 Sherbrook Street The University of Alberta is committed to the principle of equity in Winnipeg, Manitoba, Canada employment. As an employer we welcome diversity in the workplace R3A1R9 and encourage applications from all qualified women and men, Closing date for receipt of applications is February 28,1995, or until position is including Aboriginal peoples, persons with disabilities, and members of visible minorities. filled.

HEAD, DIVISION OF NEUROLOGY ST. MICHAEL'S HOSPITAL, THE UNIVERSITY OF TORONTO NEUROMUSCULAR NEUROLOGIST

The Division of Neurology at St. Michael's Hospital is seeking a Head. The Division is a major site for Undergraduate and The Division of Neurology at the Ottawa Civic Hospital, an Postgraduate training in Neurology at the University of Toronto and affiliated 700 bed teaching hospital of the University of has a special interest in Multiple Sclerosis. It is responsible for a mul- Ottawa, is seeking a Geographic Full-Time Neurologist with tidisciplinary MS Clinic which serves the population of Metropolitan expertise in Neuromuscular Disease and Electromyography. Toronto and surrounding areas. There are presently four neurologists Candidates must be Fellows of the Royal College of working in the Division which has excellent clinical, electrophysio­ logical and imaging facilities including CT and MRI. Physicians and Surgeons of Canada, must have completed one to two years of post-graduate training in the field of The appointment will be a Geographic Full-Time joint appointment Neuromuscular Disorders/Electrodiagnositc Medicine, and of St. Michael's Hospital and the University of Toronto. The suc­ must have a demonstrated commitment to teaching and cessful candidate must have demonstrated clinical and academic excellence and be capable of enhancing research activity within the clinical or basic research. Division. The FRCPC in Neurology is essential as is eligibility for Priority will be given to Canadian citizens and permanent Ontario licensure. residents of Canada in accordance with Canadian In accordance with its employment equity policy, the University of Immigration requriements. Toronto encourages applications from qualified women and men, members of visible minorities, aboriginal peoples and persons with Interested candidates should apply, enclosing a curriculum disabilities. In accordance with Canadian immigration requirements vitae and names of three references to: this advertisement is directed to Canadian citizens and permanent residents. Please forward an application including a Curriculum Vitae and the names of three referees to: Dr. L. Renaud Director, Division of Neurology Dr. J.J. Connon Physician-in-Chief Ottawa Civic Hospital St. Michael's Hospital Sector D7, Room 712 30 Bond Street 1053 Carling Avenue Toronto, Ontario Ottawa, Ontario, Canada M5B 1W8 K1Y 4E9 Closing date for applications is March 15, 1995.

Downloaded from https://www.cambridge.org/core. IP address: 170.106.35.234, on 27 Sep 2021 at 06:25:02, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0317167100040403 Intermediate Prescribing Information In women of childbearing potential, TEGRETOL should, and plasma levels of carbamazepine, and between plasma whenever possible, be prescribed as monotherapy, be­ levels and clinical efficacy or tolerability are rather tenuous, •TEGRETOL cause the incidence of congenital abnormalities in the monitoring plasma levels may be useful in the following (Carbamazepine tablets) offspring of women treated with more than one conditions: dramatic increase in seizure frequency/verifi­ antiepileptic drug is greater than in those of women cation of patient compliance; during pregnancy; when treat­ THERAPEUTIC CLASSIFICATION receiving a single antiepileptic. ing children or adolescents; in suspected absorption disor­ 1. Anticonvulsant Minimum effective doses should be given and the plasma ders; in suspected toxicity, especially where more than one levels monitored. drug is being used (see Drug Interactions). 2. For Symptomatic Relief of Trigeminal Neuralgia If pregnancy occurs in a woman receiving TEGRETOL, or Increased seizure frequency: TEGRETOL should be used 3. Antimanic if the problem of initiating TEGRETOL arises during preg­ with caution in patients with a mixed seizure disorder that nancy, the drug's potential benefits must be weighed includes atypical absence seizures, since its use has been INDICATIONS AND CLINICAL USE against its hazards, particularly during the first 3 months associated with increased frequency of generalized convul­ A. Epilepsy: TEGRETOL (carbamazepine) is indicated for of pregnancy. TEGRETOL should not be discontinued or sions. In case of exacerbation of seizures, discontinue use as an anticonvulsant drug either alone or in combination withheld if required to prevent major seizures because of TEGRETOL. with other anticonvulsant drugs. the risks posed, to mother and fetus, by status epilepticus Dermatologic: Mild skin reactions, e.g. isolated macular or Carbamazepine is not effective in controlling absence, with attendant hypoxia. maculopapular exanthema, usually disappear within a few myoclonic or atonic seizures, and does not prevent the The possibility that carbamazepine, like all major days or weeks, either during continued course of treatment generalization of epileptic discharge. Moreover, exacerba­ antiepileptic drugs, increases the risk of malformations or following a decrease in dosage. However, the patient tion of seizures may occasionally occur in patients with has been reported. There are rare reports on develop­ should be kept under close surveillance because of the rare atypical absences. mental disorders and malformations, including spina possibility of Steven-Johnson syndrome or Lyell's syn­ B. Trigeminal Neuralgia: TEGRETOL is indicated for the bifida, in association with carbamazepine. Conclusive drome occurring (see WARNINGS). symptomatic relief of pain of trigeminal neuralgia during evidence from controlled studies with carbamazepine Urinary Retention and Increased Intraocular Pressure: Be­ periods of exacerbation of true or primary trigeminal neural­ monotherapy is lacking. cause of its anticholinergic action, carbamazepine should gia (tic douloureux). It should not be used preventively Folic acid deficiency is known to occur in pregnancy. be given cautiously, if at all, to patients with increased during periods of remission. In some patients, TEGRETOL Antiepileptic drugs have been reported to aggravate folic intraocular pressure or urinary retention. Follow such has relieved glossopharyngeal neuralgia. For patients who acid deficiency, which may contribute to the increased patients closely. fail to respond to TEGRETOL, or who are sensitive to the incidence of birth defects in the offspring of treated Occurrence of Behavioral Disorders: Because it is closely drug, other accepted measures must be considered. epileptic women. Folic acid supplementation has there­ related to the othertricyclic drugs, there is some possibility Carbamazepine is not a simple analgesic and should not be fore been recommended before and during pregnancy. that carbamazepine might activate a latent psychosis, or, in used to relieve trivial facial pains or headaches. To prevent neonatal bleeding disorders, Vitamin K, ad­ elderly patients, produce agitation or confusion, especially C. Treatment of Acute Mania and Prophylaxis in Bipolar ministration to the mother the last weeks of pregnancy, when combined with other drugs. Exercise caution in (Manic-Depressive) Disorders: TEGRETOL may be used as as well as to the newborn, has been recommended. alcoholics. monotherapy or as an adjunct to lithium in the treatment of Carbamazepine passes into breast milk in concentrations Use in Patients with Cardiovascular Disorders: Use acute mania or prophylaxis of bipolar (manic-depressive) of about 25 - 60% of the plasma level. No reports are TEGRETOL cautiously in patients with a history of coronary disorders in patients resistant to or intolerant of conven­ available on the long-term effect of breast feeding. The artery disease, organic heart disease, or congestive failure. tional antimanic drugs. Carbamazepine may be a useful benefits of breast feeding should be weighed against the If a defective conductive system is suspected, an ECG alternative to neuroleptics in such patients. Patients with possible risks to the infant. Should the mother taking should be performed before administering TEGRETOL, to severe mania, dysphoric mania or rapid cycling who are carbamazepine nurse her infant, the infant must be ob­ exclude patients with atrioventricular block. non-responsive to lithium may show a positive response served for possible adverse reactions, e.g. somnolence. Driving and Operating Hazardous Machinery: Because when treated with carbamazepine. A severe hypersensitivity skin reaction in a breast-fed dizziness and drowsiness are possible side effects of Recommendations are based on extensive clinical experi­ baby has been reported. TEGRETOL, patients should be warned about the possible ence and some clinical trials versus active comparison The reliability of oral contraceptives may be adversely hazards of operating machinery or driving automobiles. agents. affected by carbamazepine (see PRECAUTIONS, Drug Drug Interactions: Induction of hepatic enzymes in re­ CONTRAINDICATIONS Interactions). sponse to carbamazepine may diminish or abolish the TEGRETOL (carbamazepine) should not be administered to PRECAUTIONS activity of certain drugs that are also metabolized in the patients with hepatic disease, a history of acute intermittent Clinical Monitoring of Adverse Reactions: TEGRETOL liver. Dosage of the following drugs may have to be porphyria, or serious blood disorder. (carbamazepine) should be prescribed only after a critical adjusted when administered with TEGRETOL: clobazam, TEGRETOL should not be administered immediately before, risk-benefit appraisal in patients with a history of cardiac, clonazepam, ethosuximide, primidone, valproic acid, in conjunction with, or immediately after a monoamine hepatic or renal damage, adverse hematological reactions alprazolam, corticosteroids (e.g. prednisolone, oxidase inhibitor. When it seems desirable to administer to other drugs, or interrupted courses of therapy with dexamethasone), cyclosporin, digoxin, doxycycline, TEGRETOL to a patient who has been receiving an MAO TEGRETOL. Careful clinical and laboratory supervision felodipine, haloperidol, thioridazine, imipramine, metha­ inhibitor, there should be as long a drug-free interval as the should be maintained throughout treatment. Should any done, oral contraceptives, theophylline, and oral anticoagu­ clinical condition allows, but in no case should this be less signs, symptoms or abnormal laboratory findings be sug­ lants (warfarin, phenprocoumon, dicumarol). than 14 days. The dosage of TEGRETOL should be low gestive of blood dyscrasia or liver disorder, TEGRETOL Phenytoin plasma levels have been reported both to be initially, and increased very gradually. should be immediately discontinued until the case is care­ raised and lowered by carbamazepine, and mephenytoin TEGRETOL should not be administered to patients present­ fully reassessed. plasma levels have been reported in rare instances to ing atrioventricular heart block. (a) Bone marrow function: Complete blood counts, includ­ increase. TEGRETOL should not be administered to patients with ing platelets and possibly reticulocytes and serum iron, The following drugs have been shown to raise plasma known hypersensitivity to carbamazepine or any tricyclic should be carried out before treatment is instituted. Sug­ carbamazepine levels: erythromycin, troleandomycin, pos­ compound, such as amitriptyline, trimipramine, imipramine, gested guidelines for monitoring are weekly for the first sibly josamycin, isoniazid, verapamil, diltiazem, or their analogues or metabolites, because of the similarity month, then monthly for the next five months, thereafter 2 propoxyphene, viloxazine, fluoxetine, cimetidine, in chemical structure. - 4 times a year. acetazolamide, danazol, and possibly desipramine. WARNINGS If low or decreased white blood cell or platelet counts are Nicotinamide raises carbamazepine plasma levels in chil­ ALTHOUGH REPORTED INFREQUENTLY, SERIOUS observed during treatment, the patient and the complete dren, but only at high dosage in adults. Since an increase ADVERSE EFFECTS HAVE BEEN OBSERVED DURING THE blood count should be monitored closely. Non-progressive in carbamazepine plasma levels may result in unwanted USEOFTEGRETOL(carbamazepine). AGRANULOCYTOSIS fluctuating asymptomatic leucopenia, which is encoun­ effects (e.g. dizziness, drowsiness, ataxia, diplopia and AND APLASTIC ANEMIA HAVE OCCURRED IN A FEW tered, does not generally call for the withdrawal of nystagmus), the dosage of TEGRETOL should be adjusted INSTANCES WITH A FATAL OUTCOME. LEUCOPENIA, TEGRETOL. Treatment should be discontinued if the patient accordingly and the blood levels monitored. THROMBOCYTOPENIA, HEPATOCELLULAR AND develops leucopenia which is progressive or accompanied Plasma levels of carbamazepine may be reduced by pheno- CHOLESTATIC JAUNDICE, AND HEPATITIS HAVE ALSO by clinical manifestations, e.g. fever or sore throat, as this barbitone, phenytoin, primidone, progabide, ortheophylline, BEEN REPORTED. IN THE MAJORITY OF CASES, could indicate the onset of significant bone marrow depres­ and possibly by clonazepam. Valproic acid, valpromide, LEUCOPENIA AND THROMBOCYTOPENIA WERE sion. and primidone have been reported to raise plasma levels of TRANSIENT AND DID NOT SIGNAL THE ONSET OF EITHER Because the onset of potentially serious blood dyscrasias the pharmacologically active metabolite, carbamazepine- APLASTIC ANEMIA OR AGRANULOCYTOSIS. TEGRETOL may be rapid, patients should be made aware of early 10,11 epoxide. The dose of TEGRETOL may consequently SHOULD BE USED CAREFULLY AND CLOSE CLINICAL AND toxic signs and symptoms of a potential hematological have to be adjusted. FREQUENT LABORATORY SUPERVISION SHOULD BE problem, as well as symptoms of dermatological or Combined use of TEGRETOL with lithium, metoclopramide, MAINTAINED THROUGHOUT TREATMENT IN ORDER TO hepatic reactions. If reactions such as fever, sore throat, or haloperidol, may increase the risk of neurotoxic side DETECT AS EARLY AS POSSIBLE SIGNS AND SYMPTOMS rash, ulcers in the mouth, easy bruising, petechial or effects (even in the presence of "therapeutic plasma OF A POSSIBLE BLOOD DYSCRASIA. TEGRETOL SHOULD purpuric hemorrhage appear, the patient should be advised levels"). BE DISCONTINUED IF ANY EVIDENCE OF SIGNIFICANT to consult his/her physician immediately. Concomitant use of TEGRETOL and isoniazid has been BONE MARROW DEPRESSION APPEARS. (See (b) Hepatic function: Baseline and periodic evaluations of reported to increase isoniazid-induced hepatotoxicity. PRECAUTIONS). hepatic function must be performed, particularly in the TEGRETOL, like other anticonvulsants, may adversely af­ SHOULD SIGNS AND SYMPTOMS SUGGEST A SEVERE elderly and patients with a history of liver disease. With­ fect the reliability of oral contraceptives; breakthrough SKIN REACTION SUCH AS STEVEN-JOHNSON SYNDROME draw TEGRETOL immediately in cases of aggravated liver bleeding may occur. Patients should accordingly be ad­ OR LYELL SYNDROME, WITHDRAW TEGRETOL AT ONCE. dysfunction or active liver disease. vised to use some alternative, non-hormonal method of LONG-TERM TOXICITY STUDIES IN RATS INDICATED A (c) Kidney function: Pretreatment and periodic complete contraception. POTENTIAL CARCINOGENIC RISK. THEREFORE WEIGH urinalysis and BUN determinations should be performed. Concomitant medication with TEGRETOL and some diuret­ THE POSSIBLE RISK AGAINST THE POTENTIAL BENEFITS (d) Ophthalmic examinations: Carbamazepine has been ics (hydrochlorothiazide, furosemide) may lead to sympto­ BEFORE PRESCRIBING TEGRETOL TO INDIVIDUAL associated with pathological eye changes. Periodic eye matic hyponatremia. PATIENTS examinations, including slit-lampfunduscopy and tonometry Carbamazepine may antagonize the effects of non-depola­ Pregnancy and nursing: Women with epilepsy who are, or are recommended. rising muscle relaxants (e.g. pancuronium); their dosage intend to become pregnant, should be treated with special (e) Plasma levels: Although correlations between dosage may need to be raised and patients should be monitored care.

Downloaded from https://www.cambridge.org/core. IP address: 170.106.35.234, on 27 Sep 2021 at 06:25:02, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0317167100040403 xvi closely for more rapid recovery from neuromuscular block­ tis, retinal changes, tinnitus, hyperacusis, and taste distur­ response is obtained. The usual optimal dosage is 800 to ade than expected. bances. 1200 mg daily. In rare instances some adult patients have Isotretinoin has been reported to alter the bioavailability Endocrine system and metabolism: Occasionally edema, received 1600 mg. As soon as disappearance of seizures and/or clearance of carbamazepine and its active 10,11- fluid retention, weight increase, hyponatremia and reduced has been obtained and maintained, dosage should be re­ epoxide; carbamazepine plasma levels should be moni­ plasma osmolality due to antidiuretic hormone (ADH)-like duced very gradually until a minimum effective dose is tored. effect occurs, leading in isolated cases to water intoxication reached. Carbamazepine, like other psycho-active drugs, may re­ accompanied by lethargy, vomiting, headache, mental con­ Children 6-12 Years of Age: Initially, 100 mg in divided duce alcohol tolerance; it is advisable to abstain from fusion, neurological abnormalities. Isolated cases of doses, increased gradually by 100 mg per day until the best alcohol during treatment. gynecomastia or galactorrhea have been reported, as well response is obtained. Dosage should generally not exceed TEGRETOL should not be administered in conjunction with as abnormal thyroid function tests (decreased L-thyroxine 1000 mg daily. As soon as disappearance of seizures has an MAO inhibitor. (See CONTRAINDICATIONS). i.e. FT„, T,,T3, and increased TSH, usually without clinical been obtained and maintained, dosage should be reduced ADVERSE REACTIONS manifestations), disturbances of bone metabolism (de­ very gradually until a minimum effective dose is reached. The reactions most frequently reported with TEGRETOL crease in plasma calcium and 25-OH-calciferol), leading in Combination Therapy: When added to existing (carbamazepine) are CNS (e.g. drowsiness, headache, un­ isolated cases to osteomalacia, as well as reports of el­ anticonvulsanttherapy, the drug should be added gradually steadiness on the feet, diplopia, dizziness), gastrointestinal evated levels of cholesterol, including HDL cholesterol and while the other anticonvulsants are maintained or gradually disturbances (nausea, vomiting), and allergic skin reac­ triglycerides. decreased, except for phenytoin, which may be increased tions. These usually occur only during the initial phase of Musculoskeletal system: Isolated cases - arthralgia, mus­ (See Precautions, Drug Interactions and Warnings, Preg­ therapy, if the initial dose is too high, or when treating cle pain or cramp. nancy and nursing). elderly patients. They have rarely necessitated discontinu­ Respiratory: Isolated cases - pulmonary hypersensitivity Use in Trigeminal Neuralgia: Initial daily dosage of 200 mg ing TEGRETOL therapy, and can be minimized by initiating characterized by fever, dyspnea, pneumonitis or pneu taken in 2 doses of 100 mg each is recommended. The total treatment at a low dosage. monia. daily dosage can be increased by 200 mg/day until relief of The occurrence of CNS adverse reactions may be a mani­ Hypersensitivity reactions. A rare delayed multi-organ pain is obtained. This is usually achieved at dosage of 200- festation of relative overdosage or significant fluctuation in hypersensitivity disorder with fever, skin rashes, vasculitis, 800 mg daily; occasionally up to 1200 mg/day may be plasma levels. In such cases it is advisable to monitor the lymphadenopathy, disorders mimicking lymphoma, necessary. As soon as relief of pain has been obtained and plasma levels and possibly lower the daily dose and/or arthralgia, leucopenia, eosinophilia, hepatosplenomegaly maintained, progressive reduction in dosage should be divide it into 3 - 4 fractional doses. and abnormal liver function tests, occurring in various attempted until a minimal effective dosage is reached. The more serious adverse reactions observed are the combinations. Other organs may also be affected (e.g. Because trigeminal neuralgia is characterized by periods of hematologic, hepatic, cardiovascular and dermatologic re­ lungs, kidneys, pancreas, myocardium). Isolated cases: remission, attempts should be made to reduce or discon­ actions, which require discontinuation of therapy. aseptic meningitis, with myoclonus and eosinophilia; tinue the use of TEGRETOL at intervals of not more than If treatment with TEGRETOL has to be withdrawn abruptly, anaphylactic reaction. Discontinue treatment should such 3 months, depending upon the individual clinical course. the change-over to another antiepileptic drug should be hypersensitivity reactions occur. Prophylactic use of the drug in trigeminal neuralgia is not effected under cover of diazepam. DOSAGE AND ADMINISTRATION recommended. The following adverse reactions have been reported: Use in Epilepsy (See INDICATIONS): TEGRETOL may be Use in Mania and Bipolar (Manic-Depressive) Disorders: Hematologic: Occasional or frequent - leucopenia; occa­ used alone or with other anticonvulsants. A low initial daily The initial daily dosage should be low, 200 to 400 mg/day, sional eosinophilia, thrombocytopenia; rare - leucocytosis, dosage of TEGRETOL with a gradual increase in dosage administered in divided doses, although higher starting lymphadenopathy; isolated cases - agranulocytosis, aplastic adjusted to the needs of the individual patient, is advised. doses of 400 to 600 mg/day may be used in acute mania. anemia, pure red cell aplasia, macrocytic anemia, TEGRETOL tablets and CHEWTABS should be taken in 2 to This dose may be gradually increased until patient megaloblastic anemia, acute intermittent porphyria, 4 divided doses daily, with meals whenever possible. symptomatology is controlled or a total daily dose of reticulocytosis, folic acid deficiency, thrombocytopenic The controlled release characteristics of TEGRETOL CR 1600 mg is achieved. Increments in dosage should be purpura, and possibly hemolytic anemia. In a few in­ reduce the daily fluctuations of plasma carbamazepine. adjusted to provide optimal patient tolerability. The usual stances, deaths have occurred. TEGRETOL CR tablets (either whole or, if so prescribed, dose range is 400 to 1200 mg/day administered in divided Hepatic: Frequent - elevated gamma-GT (due to hepatic only half a tablet) should be swallowed unchewed with a enzyme induction), usually not clinically relevant; occa­ doses. Doses used to achieve optimal acute responses and sional - elevated alkaline phosphatase; rarely transaminases; little liquid during oraftera meal. Controlled release tablets tolerability should be continued during maintenance treat­ rare - jaundice, hepatitis of cholestatic, parenchymal should be prescribed as a twice-daily dosage. If necessary, ment. When given in combination with lithium and (hepatocellular), or mixed type; isolated cases - three divided doses may be prescribed. Some patients have neuroleptics, the initial dosage should be low, 100 mg to granulomatous hepatitis. been reported to require a dosage increase when switching 200 mg daily, and then increased gradually. A dose higher from tablets to CR tablets. Dosage adjustments should be than 800 mg/day is rarely required when given in combina­ Dermatologic: Occasional to frequent - skin sensitivity individualized based on clinical response and, if necessary, tion with neurolepticsand lithium, or with other psychotropic reactions and rashes, erythematous rashes, urticaria; rare plasma carbamazepine levels. drugs such as benzodiazepines. Plasma levels are probably - exfoliative dermatitis and erythroderma, Steven-Johnson Adults and Children Over 12 Years of Age: Initially, 100 to not helpful for guiding therapy in bipolar disorders. syndrome, systemic lupus erythematosus-like syndrome; 200 mg once or twice a day depending on the severity of the Stability and Storage Recommendations isolated cases - toxic epidermal necrolysis (Lyell's syn­ case and previous therapeutic history. The initial dosage is Protect from heat and humidity. drome), photosensitivity, erythema multiform and nodosum, progressively increased, in divided doses, until the best Keep out of reach of children. skin pigmentation changes, pruritus, purpura, acne, diaphoresis, alopecia and neurodermatitis. Isolated cases of hirsuitism have been reported, however the causal rela­ AVAILABILITY OF DOSAGE FORM tionship is not clear. TEGRETOL TEGRETOL TEGRETOL TEGRETOL TEGRETOL Neurologic: Frequent - vertigo, somnolence, ataxia and tablets CHEWTABS CHEWTABS CR CR fatigue. Occasionally - an increase in motor seizures (see 200 mg 100 mg 200mg 200 mg 400 mg INDICATIONS), headache, diplopia, nystagmus, accom­ modation disorders (e.g. blurred vision); rare - abnormal Colour White Beige-orange Brownish- involuntary disorders (e.g. tremor, asterixis, orofacial red specks red specks orange dyskinesia, choreoathetosis disorders, dystonia, tics); iso­ lated cases - oculomotor disturbances, speech disorders Shape Round, flat-faced Round, flat-faced Oval, biconvex Oval, slightly Oval, slightly (e.g. dysarthria or slurred speech), peripheral neuritis, and bevel-edged and bevel-edged biconvex biconvex paraesthesia, muscle weakness. There have been some reports of paralysis and other symptoms of cerebral arterial Imprint Engraved GEIGY Engraved GEIGY Engraved GEIGY C/G engraved on CG/CG engraved insufficiency but no conclusive relationship to the adminis­ on one side and on one side and on one side and one side and H/C on one side and tration of TEGRETOL could be established. quadrasected on M/R with bisect P/U with bisect engraved on the ENE/ENE Cardiovascular: Rare - disturbances of cardiac conduction; the other on the other on the other other. engraved on the isolated cases - bradycardia, arrhythmias, Stokes-Adams Fully bisected on other. in patients with AV-block, congestive heart failure, hyper­ both sides Fully bisected tension or hypotension, aggravation of coronary artery on both sides disease, thrombophlebitis, thromboembolism. Some of these complications (including myocardial infarction and Carbamazepine 200 mg 100 mg 200 mg 200 mg 400mg arrhythmia) have been associated with other tricyclic com­ pounds. Availability Bottles of 100 & Bottles of 100 Bottles of 100 Bottles of 100 Bottles of 100 Psychiatric: Isolated cases - hallucinations (visual or 500 acoustic), depression, sometimes with talkativeness, agi­ tation, loss of appetite, restlessness, aggressive behaviour, Tegretol is a schedule F drug and can only be obtained by 4. Canger R, et al Conventional vs controlled-release car­ confusion, activation of psychosis. prescription from a licensed practitioner. Product Mono­ bamazepine; a multicentre, double-blind, cross-over Genitourinary: Isolated cases - interstitial nephritis and graph available on request. September 23,1994 study. Acta Neurol Scand 1990; 82: 9-13. renal failure, as well as signs of renal dysfunction (e.g. REFERENCES albuminuria, glycosuria, hematuria, oliguria sometimes associated with elevated blood pressure, and elevated BUN/ 1. Smith DB.etal: Results of a nationwide Veterans Adminis­ azotemia), urinary frequency, urinary retention and sexual tration cooperative study comparing the efficacy and disturbances/impotence. toxicity of carbamazepine, phenobarbital, phenytoin, and Gastrointestinal: Occasional or frequent - nausea, vomit­ primidone. Epilepsia 1987; 28(Suppl 3): 550-558. ing; occasional - dryness of the mouth and throat; rare - 2. Dooley JM: Seizures in childhood. Medicine North diarrhea or constipation; isolated cases - abdominal pain, America 1989; 4th series 2:163-172. Geigy Pharmaceuticals glossitis, stomatitis, anorexia. 3. Aldenkamp AP, et al: Controlled release carbamazepine: Division of Ciba-Geigy Canada Ltd. Sense organs: Isolated cases - lens opacities, conjunctivi­ cognitive side effeects in patients with epilepsy. Epilepsia Mississauga, Ontario L5N 2W5 or 1987; 28(5): 507-514. Dorval, Quebec H9S1B1 See pages xiv, obc. Downloaded from https://www.cambridge.org/core. IP address: 170.106.35.234, on 27 Sep 2021 at 06:25:02, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0317167100040403 xvn clearance (CLr) of gabapentin also declined with age; however, this Drug Interactions decrease can largely be explained by the decline in renal function. Antiepileptic Agents: Reduction of gabapentin dose may be required in patients who There is no interaction between Neurontin and phenytoin, have age-related compromised renal function (See Dosage and valproic acid, carbamazepine, or phenobarbital. Consequently, Administration). Neurontin may be used in combination with other commonly used antiepileptic drugs without concern for alteration of the plasma Renal Impairment concentrations of gabapentin or the other antiepileptic drugs. In patients with impaired renal function, gabapentin clearance is 100 nig, 300 mg, 400 mg Capsules markedly reduced and dosage adjustment is necessary (See Table 5 Gabapentin steady-state pharmacokinetics are similar for healthy Antiepileptic Agent in Dosage and Administration). subjects and patients with epilepsy receiving antiepileptic agents.

ACTION AND CLINICAL PHARMACOLOGY Hemodialysis: Oral Contraceptives: Gabapentin exhibits antiseizure activity in mice and rats both in the In a study in anuric subjects (N=l 1), the apparent elimination half- Coadministration of Neurontin with the oral contraceptive maximal electroshock and in the pentylenetetrazol seizure models. life of gabapentin on non-dialysis days was about 132 hours; NorlEstrin* does not influence the steady-state pharmacokinetics of dialysis three times a week (4 hours duration) lowered the apparent norethindrone or ethinyl estradiol. Gabapentin is structurally related to the neurotransmitter GABA half-life of gabapentin by about 60%, from 132 hours to 51 hours. (gamma-aminobutyric acid) but does not interact with GABA Hemodialysis thus has a significant effect on gabapentin elimination Antacids: receptors, it is not metabolized to GABA or to GABA agonists, and in anuric subjects. Coadministration of Neurontin with an aluminum and magnesium- it is not an inhibitor of GABA uptake or degradation. Gabapentin based antacid reduces gabapentin bioavailability by up to 24%. at concentrations up to 100 uM did not demonstrate affinity for Dosage adjustment in patients undergoing hemodialysis is Although the clinical significance of this decrease is not known, co­ other receptor sites such as benzodiazepine, glutamate, glycine or necessary (See Table 5 in Dosage and Administration). administration of similar antacids and gabapentin is not N-methyl-D-aspartate receptors nor does it interact with neuronal recommended. sodium channels or L-type calcium channels. Pediatric: There are no pharmacokinetic data available in children under Probenecid: The mechanism of action of gabapentin has not yet been 18 years of age. Renal excretion of gabapentin is unaltered by probenecid. established, however, it is unlike that of the commonly used anticonvulsant drugs. Hepatic Impairment Cimetidine: Because gabapentin is not appreciably metabolized in humans, A slight decrease in renal excretion of gabapentin observed when it In vitro studies with radiolabeled gabapentin have revealed a no study was performed In patients with hepatic impairment. is coadministered with cimetidine is not expected to be of clinical gabapentin binding site in rat brain tissues including neocortex and importance. hippocampus. The identity and function of this binding site remain Clinical Trials to be elucidated. In placebo-controlled trials in patients not satisfactorily controlled Use in Pregnancy with current antiepileptic drugs, Neurontin (gabapentin), when No evidence of impaired fertility or harm to the fetus due to Pharmacokinetics Adults: added to current antiepileptic therapy, was superior to placebo in gabapentin administration was revealed in reproduction studies in reducing the frequency of both simple and complex partial seizures mice at doses up to 62 times, and in rats and rabbits at doses up to Following oral administration of Neurontin (gabapentin), peak and secondarily generalized tonic-clonic seizures. Further analysis 31 times the human dose of 2400 mg/day. plasma concentrations are observed within 2 to 3 hours. Absolute of data indicated a higher efficacy for complex partial seizures and bioavailability of a 300 mg dose of Neurontin capsules is secondarily generalized tonic-clonic seizures as compared to all There are, however, no adequate and well-controlled studies in approximately 59%. At doses of 300 and 400 mg, gabapentin seizure types. Doses ranged from 900 to 1800 mg/day, with a pregnant women. Because animal reproduction studies are not bioavailability is unchanged following multiple dose administration. median dose of 1200 mg/day. always predictive of human response, this drug should only be used Gabapentin elimination from plasma is best described by linear during pregnancy if the potential benefit to the mother justifies the pharmacokinetics. The elimination half-life of gabapentin is Long-term, open, uncontrolled studies in drug-resistant patients for potential risk to the fetus. independent of dose and averages 5 to 7 hours in subjects with periods of up to 18 months demonstrated that doses up to normal renal function. 2400 mg/day did not result in anything unusal in the type or Use in Lactation frequency of adverse events. Plasma gabapentin concentrations are dose-proportional at doses of It is not known if gabapentin is excreted in human milk, and the 300 to 400 mg q8h, ranging between 1 ug/mL and 10 ug/mL, but effect on the nursing infant is unknown. However, because many INDICATIONS AND CLINICAL USE are less than dose-proportional above the clinical range (>600 mg drugs are excreted in human milk, and because of the potential for q8h). There is no correlation between plasma levels and efficacy. Neurontin (gabapentin) is indicated as adjunctive therapy for the serious adverse reactions in nursing infants from gabapentin, Gabapentin pharmacokinetics are not affected by repeated management of patients with epilepsy who are not satisfactorily breast-feeding is only recommended if the potential benefit administration, and steady state plasma concentrations are controlled by conventional therapy. outweighs the potential risks. predictable from single dose data. CONTRAINDICATIONS Use in Children Gabapentin is not appreciably metabolized in humans, is Systematic studies to establish safety and efficacy in children have Neurontin (gabapentin) is contraindicated in patients who have eliminated solely by renal excretion, and can be removed from not been performed. Data in 39 patients between the ages of 12 demonstrated hypersensitivity to the drug or to any of the plasma by hemodialysis. and 18 years included in the double-blind, placebo-controlled trials components of the formulation. showed that gabapentin was superior to placebo in reducing Gabapentin does not induce or inhibit hepatic mixed function seizure frequency. Safety data showed that the incidence of adverse PRECAUTIONS oxidase enzymes responsible for drug metabolism, does not events in this group of patients were similar to those observed in interfere with the metabolism of commonly coadministered General older individuals. antiepileptic drugs, and is minimally bound to plasma proteins. Neurontin (gabapentin) is not considered effective in the treatment of absence seizures and should therefore be used with caution in Use in the Elderly Food has no effect on the rate or extent of absorption of patients who have mixed seizure disorders that include absence Systematic studies in geriatric patients have not been conducted. gabapentin. seizures. Adverse clinical events reported among 59 patients over the age of 65 years treated with Neurontin did not differ from those reported for Table 1 summarizes the mean steady-state pharmacokinetic Tumoriaenic Potential younger individuals. The small number of individuals evaluated and parameters of Neurontin capsules. Gabapentin produced an increased incidence of acinar cell the limited duration of exposure limits the strength of any conclusions adenomas and carcinomas in the pancreas of male rats, but not reached about the influence of age, if any, on the kind and incidence Table 1: Summary of Neurontin {gabapentin} Mean Steady-State female rats or in mice, in oncogenic studies with doses of of adverse events associated with the use of Neurontin. Pharmacokinetic Parameters in Adults Following Q8H Administration 2000 mg/kg which resulted in plasma concentrations 14 times Pharmacokinetic 300 mg 400 mg higher than those occurring in humans at the maximum As Neurontin is eliminated primarily by renal excretion, dosage Parameter (N = 7) (N=ll) recommended dose of 2400 mg/day. The relevance of these adjustment may be required in elderly patients because of declining pancreatic acinar cell tumours in male rats to humans is unknown, renal function (See Dosage and Administration). ^max (pg/mL) 4.02 5.50 particularly since tumours of ductal rather than acinar cell origin are 'max (hr) 2.7 2.) the predominant form of human pancreatic cancer. Use in Renal Impairment Gabapentin clearance is markedly reduced in this patient tV2 (hr) 5.2 6.1 Drug Discontinuation population and dosage reduction is necessary (See Table 5 in AUC(o-ot) (pg'hr/mL) 24.8 33.3 As with other anticonvulsant agents, abrupt withdrawal is not Dosage and Administration). AE%' NA 63.6 recommended because of the possibility of increased seizure frequency. When in the judgement of the clinician there is a need for dose laboratory Tests 1 Amount excreted in urine {% of dose) reduction, discontinuation or substitution with alternative medication, Clinical trials data do not indicate that routine monitoring of clinical NA = Not available this should be done gradually over a minimum of one week. laboratory parameters is necessary for the safe use of Neurontin. In patients with epilepsy, gabapentin concentrations in Neurontin may be used in combination with other commonly used cerebrospinal fluid are approximately 20% of corresponding Occupational Hazards antiepileptic drugs without concern for alteration of the blood steady-state trough plasma concentrations. Patients with uncontrolled epilepsy should not drive or handle concentrations of gabapentin or other antiepileptic drugs. potentially dangerous machinery. During clinical trials, the most Elderly: common adverse reactions observed were somnolence, ataxia, For urinary protein determination the sulfosalicylic acid precipitation Apparent oral clearance (CL/F) of gabapentin decreased as age fatigue and nystagmus. Patients should be advised to refrain from procedure is recommended, as false positive reodings were increased, from about 225 mL/min in subjects under 30 years of activities requiring mental alertness or physical coordination until reported with the Ames N-Multistix SG® dipstick test, when age to about 125 mL/min in subjects over 70 years of age. Renal they are sure that Neurontin does not affect them adversely. gabapentin or placebo was added to other anticonvulsant drugs. Downloaded from https://www.cambridge.org/core. IP address: 170.106.35.234, on 27 Sep 2021 at 06:25:02, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0317167100040403 XV111 ADVERSE REACTIONS Withdrawal From Treatment Due to Adverse Events Dosage adjustment in elderly patients due to declining renal function Approximately 6.4% of the 543 patients who received Neurontin in and in patients with renal impairment or undergoing hemodialysis is Incidence in Controlled Clinical Trials the placebo-controlled studies withdrew due to adverse events. In recommended as follows: Table 2 lists treatment-emergent signs and symptoms that occurred comparison, approximately 4.5% of the 378 placebo-controlled in at least 1% of patients with partial seizures participating in participants withdrew due to adverse events during these studies. Table 5: Maintenance Dosage of Neurontin in Adults placebo-controlled studies. In these studies, either Neurontin (at The adverse events most commonly associated with withdrawal were With Reduced Renal Function doses of 600, 900, 1200 or 1800 mg/day) or placebo were added somnolence (1.2%), ataxia (0.8%), fatigue, nausea and/or vomiting to the patient's current antiepileptic drug therapy. and dizziness (all at 0.6%). Renal Function Total Creatinine Clearance Daily Dose Dose Regimen The most commonly observed adverse events associated with the use (mL/min) (mg/day) (mg) of Neurontin in combination with other antiepileptic drugs, not seen Other Adverse Events Observed in All Clinical Trials at an equivalent frequency in placebo-treated patients, were Adverse events that occurred in at least 1% of the 2074 individuals >60 1200 400 Three times a day somnolence, dizziness, ataxia, fatigue, nystagmus and tremor. who participated in all clinical trials are described below, except 30-60 600 300 Twice a Day those already listed in the previous table: 15-30 300 300 Once a Day Among the treatment-emergent adverse events occurring in Body As a Whole aesthenia, malaise, facial edema <15 150 300 Once Daily Every Neurontin-treated patients, somnolence and ataxia appeared to Other Day exhibit a positive dose-response relationship. Patients treated with Cardiovascular System hypertension Hemodialysis 200-300b 1800 mg/day (n=54, from one controlled study) experienced Digestive System anorexia, flatulence, gingivitis approximately a two-fold increase, as compared to patients on Hematologic and a Loading dose of 300 to 400 mg lower doses of 600 to 1200 mg/day (n=489, from several Lymphatic System purpura; most often described as controlled studies), in the incidence of nystagmus (20.4%), tremor ° Maintenance dose of 200 to 300 mg Neurontin following each 4 bruises resulting from physical (14.8%), rhinitis (13%), peripheral edema (7.4%), abnormal hours of hemodialysis trauma coordination, depression and myalgia (all at 5.6%). Adverse events Musculoskeletal System arthralgia were usually mild to moderate in intensity, with a median time to Children Over 12 Years of Age resolution of 2 weeks. Nervous System vertigo, hyperkinesia, The dosage used in a limited number of patients in this age group paresthesia, anxiety, hostility, was 900-1200 mg/day. Doses above 1200 mg/day have not Since Neurontin was administered most often in combination with been investigated. decreased or absent reflexes other antiepileptic agents, it was not possible to determine which Respiratory System pneumonia agent(s) was associated with adverse events. AVAILABILITY OF DOSAGE FORMS Special Senses abnormal vision Neurontin (gabapentin) capsules are supplied as fellows: Table 2: Treatment-Emergent Adverse Event Incidence in Placebo- Controlled Add-On Trials (Events in at Least 1% of Neurontin SYMPTOMS AND TREATMENT OF OVERDOSAGE 100-mg capsules; Patients and Numerically More Frequent than in the Placebo Group) 8 Acute, life-threatening toxicity has not been observed with Hard gelatin SUPRO capsules with white opaque body and cap Neurontin (gabapentin) overdoses of up to 49 grams ingested at printed with "PD" on one side and "Neurontin/100 mg" on the Neurontin0 Placebo0 BODY SYSTCM/ N = 543 N = 378 one time. In these cases, double vision, slurred speech, drowsiness, other. Bottles of 100 capsules. ADVERSE EVENT (AE) % % lethargy and diarrhea were observed. All patients recovered with supportive care. 300-mg capsules; BODY AS A WHOLE: 9 Hard gelatin SUPRO capsules with yellow opaque body and cap Fatigue 11.0 5.0 Gabapentin can be removed by hemodialysis. Although printed with "PD* on one side and "Neurontin/300 mg" on the Weight Increase 2.9 1.6 hemodialysis has not been performed in the few overdose cases Back Pain 1.8 0.5 other. Bottles of 100 capsules. Peripheral Edema 1.7 0.5 reported, it may be indicated by the patients clinical state or in patients with significant renal impairment. 400-mg capsules; CARDIOVASCULAR: Hard gelatin SUPRO3 capsules with orange opaque body and cap Vasodilatation 1.1 0.3 Reduced absorption of gabapentin at higher doses may limit drug printed with "PD* on one side and "Neurontin/400 mg* on the DIGESTIVE SYSTEM: absorption at the time of overdosing and, hence, reduce toxicity other. Bottles of 100 capsules. Dyspepsia 2.2 0.5 from overdoses. Dry Mouth or Throat 1.7 0.5 Composition Constipation 1.5 0.8 An oral lethal dose of gabapentin was not identified in mice and Capsules contain gabapentin, lactose, corn starch, and talc. Dental Abnormalities 1.5 0.3 rats given doses as high as 8000 mg/kg. Signs of acute toxicity in Capsule shells may contain gelatin, titanium dioxide, silicon dioxide, Increased Appetite 1.1 0.8 animals included ataxia, laboured breathing, ptosis, hyperactivity, or sodium lauryl sulfate, yellow iron oxide, red iron oxide, and FD&C excitation. HEMATOLOGIC AND Blue No. 2. LYMPHATIC SYSTEMS: Leukopenia 1.1 0.5 DOSAGE AND ADMINISTRATION Stability and Storage Recommendations MUSCULOSKELETAL SYSTEM: Adults Store at controlled room temperature 15-30°C. Myalgia 2.0 1.9 The usual effective maintenance dose is 900 to 1200 mg/day. Fracture 1.1 0.8 Treatment should be initiated with 300 to 400 mg/day. Titration to NERVOUS SYSTEM: an effective dose, in increments of 300 mg or 400 mg/day, can Somnolence 19.3 8.7 progress rapidly and can be accomplished over three days (see Dizziness 17.1 6.9 Table 3). Neurontin is given orally with or without food. Ataxia 12.5 5.6 Nystagmus 8.3 4.0 Table 3. Titration Schedule Tremor 6.8 3.2 NEW Nervousness 2.4 1.9 DOSE Day 1 Day 2 Day 3 Dysarthria 2.4 0.5 Amnesia 2.2 0.0 900 mg/day 300 mg OD 300 mg BID 300 mg TID NEURONTIN Depression 1.8 1.8 1200 mg/day 400 mg OD 400 mg BID 400 mg TID Abnormal Thinking 1.7 1.3 ADDED SEIZURE CONTROL... Twitching 1.3 0.5 Data from clinical trials suggest that doses higher than Abnormal Coordination 1.1 0.3 1200 mg/day may have increased efficacy in some patients; RESPIRATORY SYSTEM: however, higher doses may also increase the incidence of adverse Rhinitis 4.1 3.7 events (See Adverse Reactions). Pharyngitis 2.8 1.6 Coughing 1.8 1.3 Daily maintenance doses should be given in three equally divided SKIN AND APPENDAGES: doses (See Table 4), and the maximum time between doses in a Abrasion 1.3 0.0 three times daily schedule should not exceed 12 hours. It is not Pruritus 1.3 0.5 necessary to monitor gabapentin plasma concentrations in order to optimize Neurontin therapy. Further, as there are no drug UROGENITAL SYSTEM: Impotence 1.5 1.1 interactions with commonly used antiepileptic drugs, Neurontin may be used in combination with these drugs without concern for .EASY TO HANDLE SPECIAL SENSES: alteration of plasma concentrations of either gabapentin or other Diplopia 5.9 1.9 antiepileptic drugs. Amblyopia 4.2 1.1

LABORATORY DEVIATIONS: Table 4. Maintenance Dosage Schedule WBC Decreased 1.1 0.5 0 PAAB Total Daily Dose (mg/day) Schedule Recycled Paper CCPP a Plus background antiepileptic drug therapy 900 300 mg TID 1200 400 mg TID Data from long-term, open, uncontrolled studies shows that PARKE-DAVIS Neurontin treatment does not result in any new or unusual adverse 1800 2 x 300 mg TID Scarborough. Ontario, MIL 2N3 events. 2400 2 x 400 mg TID • T.M. Warner-Lambert Company. Parke-Davis Division, Warner-Lambert Canada Inc., auth, user. Downloaded from https://www.cambridge.org/core. IP address: 170.106.35.234, on 27 Sep 2021 at 06:25:02, subject to the Cambridge Core terms of use, available at 94-6E https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0317167100040403 See pages ix, xiii. Liver function tests should be performed prior to therapy and at fre­ proex sodium) dosage or withdrawal of therapy pending investiga­ quent intervals thereafter especially during the first 6 months. tion. However, physicians should not rely totally on serum biochemistry Hyperammonemia with or without lethargy or coma has been since these tests may not be abnormal in all instances, but should reported and may be present in the absence of abnormal liver func­ also consider the results of careful interim medical history and tion tests; if elevation occurs the divalproex sodium should be dis­ physical examination. Caution should be observed when adminis­ continued. ^m (divalproex sodium) 0 tering EPIVAL to patients with a prior history of hepatic disease. EPIVAL" (divalproex sodium) is partially eliminated in the urine as a Patients with various unusual congenital disorders, those with ketone-containing metabolite which may lead to a false interpreta­ PRESCRIBING INFORMATION severe seizure disorders accompanied by mental retardation, and tion of the urine ketone test. those with organic brain disease may be at particular risk. There have been reports of altered thyroid function tests associated NAME OF DRUG: EPIVAL" (divalproex sodium) In high-risk patients, it might also be useful to monitor serum fi­ Enteric-Coated Tablets with valproic acid: the clinical significance of these is unknown. brinogen and albumin for decreases in concentration and serum Renal Impairment: Renal impairment is associated with an increase THERAPEUTIC CLASSIFICATION: Anticonvulsant ammonia for increases in concentration. If changes occur, dival­ in the unbound fraction of valproate. In several studies, the unbound proex sodium should be discontinued. Dosage should be titrated to 0 fraction of valproate in plasma from renally impaired patients was ACTION AND CLINICAL PHARMACOLOGY: EPIVAL (divalproex and maintained at the lowest dose consistent with optimal seizure approximately double that for subjects with normal renal function. sodium) has anticonvulsant properties, and is chemically related to control. valproic acid. Although its mechanism of action has not yet been Hemodialysis in renally impaired patients may remove up to 20% of The drug should be discontinued immediately in the presence of established, it has been suggested that its activity is related to the circulating valproate. significant hepatic dysfunction, suspected or apparent. In some increased brain levels of gamma-aminobutyric acid (GABA). The Use in the Elderly: The safety and efficacy of EPIVAL" in elderly cases, hepatic dysfunction has progressed in spite of discontinua­ effect on the neuronal membrane is unknown. EPIVAL" dissociates patients with epilepsy and mania has not been systematically evalu­ tion of drug. The frequency of adverse effects (particularly elevated into valproic acid in the gastrointestinal tract. ated in clinical trials. Caution should thus be exercised in dose selec­ liver enzymes) may increase with increasing dose. The benefit of Peak serum levels of valproic acid occur in 3 to 4 hours. tion for an elderly patient, recognizing the more frequent hepatic improved symptom control at higher doses should therefore be The serum half-life (ti/j) of valproic acid is typically in the range of 6 and renal dysfunctions, and limited experience with EPIVAL0 in this weighed against the possibility of a greater incidence of adverse to 16 hours. Half-lives in the lower part of the above range are usu­ population. effects. ally found in patients taking other drugs capable of enzyme induc­ Driving and Hazardous Occupations: EPIVAL0 (divalproex sodium) tion. Enzyme induction may result in enhanced clearance of valproic Use in pregnancy: According to recent reports in the medical liter­ may produce CNS depression, especially when combined with acid by glucuronidation and microsomal oxidation. Because of ature, valproic acid may produce teratogenicity in the offspring of another CNS depressant, such as alcohol. Therefore, patients these changes in valproic acid clearance, monitoring of valproate human females receiving the drug during pregnancy. The incidence and concomitant drug concentrations should be intensified when­ of neural tube defects in the fetus may be increased in mothers should be advised not to engage in hazardous occupations, such as ever enzyme-inducing drugs are introduced or withdrawn. A slight receiving valproic acid during the first trimester of pregnancy. Based driving a car or operating dangerous machinery, until it is known delay in absorption occurs when the drug is administered with upon a single report, it was estimated that the risk of valproic acid- that they do not become drowsy from the drug. meals but this does not affect the total absorption. Valproic acid is exposed women having children with spina bifida is approximately Drug Interactions: EPIVAL" (divalproex sodium) may potentiate the rapidly distributed throughout the body and the drug is strongly 1-2%. This risk is similar to that which applies to non-epileptic CNS depressant action of alcohol. bound (90%) to human plasma proteins. Increases in doses may women who have had children with neural tube defects (ANEN- The concomitant administration of valproic acid with drugs that result in decreases in the extent of protein binding and variable CEPHALY AND SPINA BIFIDA). exhibit extensive protein binding (e.g., aspirin, carbamazepine and changes in valproic acid clearance and elimination. In epilepsy, the Animal studies have demonstrated valproic acid-induced terato­ dicumarol) may result in alteration of serum drug levels. therapeutic plasma concentration range is believed to be from 50 to genicity (see Reproduction and Teratology under TOXICOLOGY), Aspirin and Warfarin: Caution is recommended when EPIVAL0 is 100 pg/mL. Occasional patients may be controlled with serum lev­ and studies in human females have demonstrated placental transfer administered with drugs affecting coagulation (e.g., aspirin and els lower or higher than this range. A good correlation has not been of the drug. warfarin). (See ADVERSE REACTIONS.) established between daily dose, serum level and therapeutic effect. Multiple reports in the clinical literature indicate an association Phenobarbital: There is evidence that valproic acid may cause an In placebo-controlled clinical studies in acute mania, 79% of between the use of antiepileptic drugs and an elevated incidence of increase in serum phenobarbital levels, by impairment of non-renal patients were dosed to a plasma concentration between 50 ug/mL birth defects in children born to epileptic women taking such med­ clearance. This phenomenon can result in severe CNS depression. and 125 ug/mL. Protein binding of valproate is saturable ranging ication during pregnancy. The incidence of congenital malforma­ The combination of valproic acid and phenobarbital has also been from 90% at 50 pg/mL to 82% at 125 gg/mL tions in the general population is regarded to be approximately 2%; reported to produce CNS depression without significant elevations Elimination of valproic acid and its metabolites occurs principally in in children of treated epileptic women, this incidence may be of barbiturate or valproic acid serum levels. Patients receiving con­ the urine, with minor amounts in the feces and expired air. Very lit­ increased 2 to 3-fold. The increase is largely due to specific defects, comitant barbiturate therapy should be closely monitored for neu­ tle unmetabolized parent drug is excreted in the urine. The principal e.g. congenital malformations of the heart, cleft lip and/or palate, rological toxicity. Serum barbiturate drug levels should be obtained, metabolite formed in the liver is the glucuronide conjugate. Other craniofacial abnormalities and neural tube defects. Nevertheless, if possible, and the barbiturate dosage decreased, if indicated. metabolites in the urine are products of C-3, C-4 and C-5 oxidation. the great majority of mothers receiving antiepileptic medications Primidone: Primidone is metabolized into a barbiturate, and there­ The major oxidative metabolite in the urine is 2-propyl-3-keto-pen- deliver normal infants. fore, may also be involved in a similar or identical interaction. tanoic acid; minor metabolites are 2-propyl-glutaric acid, 2-propyl- Data are more extensive with respect to diphenylhydantoin and Phenytoin:There is conflicting evidence regarding the interaction of 5-hydroxy-pentanoic acid, 2-propyl-3-hydroxy-pentanoic acid and phenobarbital, but these drugs are also the most commonly pre­ valproic acid with phenytoin. It is not known if there is a change in 2-propyl-4-hydroxy-pentanoicacid. scribed antiepileptics. Some reports indicate a possible similar unbound (free) phenytoin serum levels. The dosage of phenytoin (See WARNINGS regarding statement on fatal hepatic dysfunction.) association with the use of other antiepileptic drugs, including should be adjusted as required by the clinical situation. There have trimethadione, paramethadione, and valproic acid. However, the been reports of breakthrough seizures occurring with the combina­ INDICATIONS AND CLINICAL USE: possibility also exists that other factors, e.g. genetic predisposition tion of valproic acid and phenytoin. Epilepsy: EPIVAL0 (divalproex sodium) is indicated for use as sole or the epileptic condition itself may contribute to or may be mainly or adjunctive therapy in the treatment of simple or complex absence responsible for the higher incidence of birth defects. Because EPIVAL" (divalproex sodium) may interact with concur­ seizures, including petit mal and is useful in primary generalized Patients taking valproic acid may develop clotting abnormalities. If rently administered drugs which are capable of enzyme induction, seizures with tonic-clonic manifestations. Divalproex sodium may valproic acid is used in pregnancy, the clotting parameters should periodic serum level determinations of these drugs are recom­ also be used adjunctive^ in patients with multiple seizure types be monitored carefully. mended during the early part of therapy. which include either absence or tonic-clonic seizures. Antiepileptic drugs should not be discontinued in patients to whom Clonazepam: The concomitant use of valproic acid and clonazepam Acute Mania: EPIVAL0 (divalproex sodium) is indicated in the treat­ the drug is administered to prevent major seizures, because of the may produce absence status in patients with a history of absence- ment of the manic episodes associated with bipolar disorder (DSM- strong possibility of precipitating status epilepticus with attendant type seizures. hypoxia and risks to both the mother and the unborn child. With lll-R). Oral contraceptives: Evidence suggests that there is an association regard to drugs given for minor seizures, the risks of discontinuing The effectiveness of EPIVAL0 in long-term use, that is for more than between the use of certain drugs capable of enzyme induction and medication prior to or during pregnancy should be weighed against 3 weeks, has not been systematically evaluated in controlled trials. failure of oral contraceptives. One explanation for this interaction is the risk of congenital defects in the particular case and with the par­ that enzyme-inducing antiepileptic drugs effectively lower plasma EPIVAL" is not indicated for use as a mood stabilizer in patients ticular family history. under 18 years of age. concentrations of the relevant steroid hormones, resulting in unim­ Epileptic women of childbearing age should be encouraged to seek paired ovulation. However, other mechanisms, not related to 0 the counsel of their physician and should report the onset of preg­ CONTRAINDICATIONS: EPIVAL (divalproex sodium) should not be enzyme induction, may contribute to the failure of oral contracep­ nancy promptly to him. Where the necessity for continued use of administered to patients with hepatic disease or significant dys­ tives. Valproic acid is not a significant enzyme inducer and would antiepileptic medication is in doubt, appropriate consultation is function; it is contraindicated in patients with known hypersensitiv­ not be expected to decrease concentrations of steroid hormones. indicated. ity to the drug. However, clinical data about the interaction of valproic acid with Risk-benefit must be carefully considered when treating women of oral contraceptives are minimal. WARNINGS: Hepatic failure resulting in fatalities has occurred in childbearing age for bipolar disorder. patients receiving valproic acid and its derivatives. These incidences Tests to detect neural tube and other defects using current accept­ Seizures: In addition to enhancing central nervous system (CNS) usually occurred during the first six months of treatment with val­ ed procedures should be considered a part of routine prenatal care depression when used concurrently with valproic acid, tricyclic proic acid. Experience has indicated that children under the age of in childbearing women receiving valproate. antidepressants, MAO Inhibitors, and antipsychotics may lower the two years are at a considerably increased risk of developing fatal Use in Nursing Mothers: Valproic acid is excreted in breast milk. seizure threshold. Dosage adjustments may be necessary to con­ hepatotoxicity, especially those on multiple anticonvulsants, those Concentrations in breast milk have been reported to be 1 to 10% of trol seizures. with congenital metabolic disorders, those with severe seizure dis­ serum concentrations. As a general rule, nursing should not be Carbamazepine: Concomitant use of carbamazepine with valproic orders accompanied by mental retardation, and those with organic undertaken while a patient is receiving EPIVAL" (divalproex sodi­ acid may result in decreased serum concentrations and halt-life of brain disease. um). It is not known what effect this may have on a nursing infant. valproate due to increased metabolism induced by hepatic micro­ The risk in this age group decreased considerably in patients receiv­ Fertility: The effect of valproate on testicular development and on somal enzyme activity. Valproate causes an increase in the active ing valproate as monotherapy. Similarly, patients aged 3 to 10 years sperm production and fertility in humans is unknown. (See TOXI­ 10,11 -epoxide metabolite of carbamazepine by inhibition of its were at somewhat greater risk if they received multiple anticonvul­ COLOGY: Fertility, for results in animal studies.) breakdown. Monitoring of serum concentrations is recommended sants than those who received only valproate. Risk generally Long-term animal toxicity studies indicate that valproic acid is a when either medication is added to or withdrawn from an existing declined with increasing age. No deaths have been reported in weak carcinogen or promoter in rats and mice. The significance of regimen. Changes in the serum concentration of the 10,11 -epox­ patients over 10 years of age who received valproate alone, these findings for man is unknown at present. 0 ide metabolite of carbamazepine, however, will not be detected by if EPIVAL is to be used for the control of seizures in children two routine serum carbamazepine assay. years old or younger, it should be used with extreme caution and as PRECAUTIONS: a sole agent. The benefits of therapy should be weighed against the Cimetidine: Cimetidine may decrease the clearance and increase the risks. Hepatic dysfunction: See CONTRAINDICATIONS and WARNINGS. half-life of valproic acid by altering its metabolism. In patients Serious or fatal hepatotoxicity may be preceded by non-specific General: Because of reports of thrombocytopenia, inhibition of the receiving valproic acid, serum valproic acid levels should be moni­ symptoms such as malaise, weakness, lethargy, facial edema, second phase of platelet aggregation, platelet counts and coagula­ tored when treatment with cimetidine is instituted, increased, anorexia, vomiting, and in epileptic patients, loss of seizure control. tion tests are recommended before instituting therapy and at peri­ decreased, or discontinued. The valproic acid dose should be adjusted accordingly. Patients and parents should be instructed to report such symp­ odic intervals. It is recommended that patients receiving EPIVAL" toms. Because of the non-specific nature of some of the early signs, (divalproex sodium) be monitored for platelet count and coagula­ Chlorpromazine: A single study has shown that the concomitant hepatotoxicity should be suspected in patients who become unwell, tion parameters prior to planned surgery. use of chlorpromazine with valproic acid may result in a decrease in other than through obvious cause, while taking EPIVAL0 (dival­ Clinical evidence of hemorrhage, bruising or a disorder of hemosta- valproic acid clearance. Valproic acid serum concentrations and proex sodium). sis/coagulation is an indication for reduction of EPIVAL" (dival­ effects should be monitored when valproic acid is co-administered

Downloaded from https://www.cambridge.org/core. IP address: 170.106.35.234, on 27 Sep 2021 at 06:25:02, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0317167100040403 XX with chlorpromazine due to possible inhibition of valproic acid were somnolence (31 %), tremor (29%), headache (24%), asthenia from an initial low level. The tablets should be swallowed without metabolism. (23%), diarrhea (22%), and nausea (20%). chewing. Selective serotonin re-uptake inhibitors (SSRIs): Some evidence Associated with Discontinuation ol Treatment: In the placebo-con­ Acute Mania: The recommended initial dose is 250 mg three times suggests that SSRIs inhibit the metabolism of valproate, resulting trolled trials, adverse events which resulted in valproate discontinu­ a day. The dose should be increased as rapidly as possible to in higher than expected levels of valproate. ation in at least one percent of patients were nausea (4%), achieve the lowest therapeutic dose which produces the desired Tricyclic antidepressants: The metabolism of amitriptyline and nor­ abdominal pain (3%), somnolence (2%), and rash (2%). clinical effect or the desired range of plasma concentrations. triptyline after a single dose of amitriptyline (50 mg) was inhibited In the long-term retrospective trials, adverse events which resulted In placebo-controlled trials, 84% of patients received and tolerated by multiple dosing with valproic acid (500 mg twice daily) in sixteen in valproate discontinuation in at least one percent of patients were maximum daily doses of between 1000 mg/day to 2500 mg/day. healthy male and female volunteers. For the sum of amitriptyline alopecia (2.4%), somnolence (1.9%), nausea (1.7%), and tremor The maximum recommended dosage is 60 mg/kg/day. and nortriptyline plasma concentrations, in the presence of valproic (1.4%). The time to onset of these events was generally within the The relationship of plasma concentration to clinical response has first two months of initial exposure to valproate. A notable excep­ not been established for EPIVAL". In controlled clinical studies, acid, the mean Cmax and AUC were increased by 19% and 42%, respectively. tion was alopecia, which was first experienced after 3-6 months of 79% of patients achieved and tolerated serum valproate concentra­ exposure by 8 of the 15 patients who discontinued valproate in tions between 50 pg/mL and 125 pg/mL. Lithium: In a double-blind, placebo-controlled, multiple dose response to the event. When changing therapy involving drugs known to induce hepatic crossover study in 16 healthy male volunteers, pharmacokinetic microsomal enzymes (e.g., carbamazepine) or other drugs with Controlled Trials: 1MB 1 summarizes those treatment-emergent parameters of lithium were not altered by the presence or absence valproate interactions (see PRECAUTIONS, Drug Interactions), it is adverse events reported for patients in the placebo-controlled trials of EPIVAL°. The presence of lithium, however, resulted in an 11%- advisable to monitor serum valproate concentrations. when the incidence rate in the divalproex sodium group was at least 12% increase in the AUC and C of valproate. T was also Conversion from Depakene' to EPIVAL': EPIVAL" (divalproex sodi­ max max 5%. (Maximum treatment duration was 21 days; maximum dose in reduced. Although these changes were statistically significant, they um) dissociates into valproic acid in the gastrointestinal tract. 83% of patients was between 1000 mg - 2500 mg per day). are not likely to have clinical importance. Divalproex sodium tablets are uniformly and reliably absorbed, Benzodiazepines: Valproic acid may decrease oxidative liver metab­ Table 1 however, because of the enteric-coating, absorption is delayed by olism of some benzodiazepines, resulting in increased serum con­ Treatment-Emergent Adverse Event Incidence (> 5%) in Short- an hour when compared with Depakene (valproic acid) capsules. centrations. In two small studies in healthy volunteers, valproate Term Placebo-Controlled Trials The bioavailability of divalproex sodium tablets is equivalent to that produced a 17% decrease in the clearance of lorazepam, and 26% of Depakene (valproic acid) capsules. Body System/Event Percentage of Patients 0 decrease in the clearance of unbound diazepam. Displacement of In patients previously receiving Depakene (valproic acid) therapy, divalproex sodium 0 diazepam from plasma protein binding sites may also occur. During placebo EPIVAL should be initiated at the same daily dose and dosing (N=89) (N=97) valproate administration the unbound fraction of diazepam in the schedule. After the patient is stabilized on EPIVAL", a dosing sched­ serum increased approximately twofold. Body as a Whole ule of two or three times a day may be elected in selected patients. Headache 21.3 30.9 ADVERSE REACTIONS: Pain 14.6 15.5 PHARMACEUTICAL INFORMATION: Epilepsy: The most commonly reported adverse reactions are nau­ Accidental injury 11.2 5.2 Drug Substance sea, vomiting and indigestion. Since valproic acid has usually been Asthenia 10.1 0 7.2 Tradename: EPIVAL used with other antiepileptics, it is not possible in most cases to Abdominal Pain 9.0 8.2 determine whether the adverse reactions mentioned in this section Back Pain 5.6 6.2 Proper Name: Divalproex sodium are due to valproic acid alone or to the combination of drugs. Digestive System USAN Names: INN: Valproate semisodium Gastrointestinal: Nausea, vomiting and indigestion are the most Nausea 22.5 15.5 BAN: Semisodium valproate commonly reported side effects at the initiation of therapy. These Vomiting 12.4* 3.1 Chemical Name: Sodium hydrogen bis (2-propylpentanoate) or effects are usually transient and rarely require discontinuation of Diarrhea 10.1 13.4 therapy. Diarrhea, abdominal cramps and constipation have also Dyspepsia 9.0 8.2 Sodium hydrogen bis (2-propylvalerate)

been reported. Anorexia with some weight loss and increased Constipation 7.9 8.2 Molecular Weight: 310.14 Molecular Formula: C„Hj,Na04 appetite with some weight gain have also been seen. Nervous System Structural Formula: Somnolence 19.1 12.4 CNS Effects: Sedative effects have been noted in patients receiving CH3CH2CH2 CH~—CH2CH2CH3 valproic acid alone but are found most often in patients on combi­ Dizziness 12.4 4.1 nation therapy. Sedation usually disappears upon reduction of other Tremor 5.6 6.2 antiepileptic medication. Ataxia, headache, nystagmus, diplopia, Respiratory System asterixis, "spots before the eyes", tremor (may be dose-related), Pharyngitis 6.7 9.3 dysarthria, dizziness, and incoordination have rarely been noted. Skin and Appendages Rare cases of coma have been reported in patients receiving val­ Rash 5.6 3.1 I CH3CH2CH2— CH — CH2CH2CH3 proic acid alone or in conjunction with phenobarbital. "Statistically significant at p<0.05 level. Description: Divalproex sodium is a stable coordination compound Dermatologic: Transient increases in hair loss have been observed. Adverse Events in Elderly Patients: In elderly patients (above 65 comprised of sodium valproate and valproic acid in a 1:1 molar Skin rash, photosensitivity, generalized pruritus, erythema multi­ years of age), there were more frequent reports of accidental injury, relationship and formed during the partial neutralization of valproic forme, Stevens-Johnson syndrome and petechiae have rarely been infection, pain, and to a lesser degree, somnolence and tremor, acid with 0.5 equivalent of sodium hydroxide. It is a white powder noted. when compared to patients 18-65 years of age. Somnolence and with a characteristic odor, freely soluble in many organic solvents tremor tended to be associated with the discontinuation of val­ Endocrine: There have been reports of irregular menses and sec­ and in aqueous alkali solutions. ondary amenorrhea, breast enlargement, galactorrhea and parotid proate. Non-Medicinal Ingredients: EPIVAL" Enteric-Coated Tablets: gland swelling in patients receiving valproic acid. Abnormal thyroid SYMPTOMS AND TREATMENT OF OVERDOSAGE: In a reported Cellulosic polymers, silica gel, diacetylated monoglycerides, povi­ function tests have been reported (see PRECAUTIONS). case of overdosage with valproic acid after ingesting 36 g in combi­ done, pregelatinized starch (contains corn starch), talc, titanium Psychiatric: Emotional upset, depression, psychosis, aggression, nation with phenobarbital and phenytoin, the patient presented in dioxide, and vanillin. hyperactivity and behavioral deterioration have been reported. deep coma. An EEG recorded diffuse slowing, compatible with the In addition, individual tablets contain: Musculoskeletal: Weakness has been reported. state of consciousness. The patient made an uneventful recovery. 125 mg tablets: FD&C Blue No.1 and FD&C Red No. 40 Hematopoietic:Thrombocytopenia has been reported. Valproic acid Naloxone has been reported to reverse the CNS depressant effects 250 mg tablets: FD&C Yellow No. 6 and iron oxide inhibits the second phase of platelet aggregation (see PRECAU­ of valproic acid overdosage. 500 mg tablets: D&C Red No. 30, FD&C Blue No. 2, and iron oxide. TIONS). This may be reflected in altered bleeding time. Petechiae, Because naloxone could theoretically also reverse the antiepileptic Storage Recommendations: Store between 15°- 30°C (59°- 86°F). bruising, hematoma formation and frank hemorrhage have been effects of EPIVAL®, it should be used with caution in patients with reported. Relative lymphocytosis, macrocytosis and hypofibrino- epilepsy. AVAILABILITY OF DOSAGE FORMS: EPIVAL-' (divalproex sodium) genemia have been noted. Leukopenia and eosinophilia have also Since EPIVAL0 tablets are enteric-coated, the benefit of gastric particle coated tablets are available as salmon-pink coloured tablets been reported. Anemia, including macrocytic with or without folate lavage or emesis will vary with the time since ingestion. General of 125 mg in bottles of 100 tablets; peach-coloured tablets of deficiency, bone marrow suppression and acute intermittent por­ supportive measures should be applied with particular attention to 250 mg and lavender-coloured tablets of 500 mg in bottles of 100 phyria have been reported. the prevention of hypovolemia and the maintenance of adequate and 500 tablets. urinary output. Hepatic: Minor elevations of transaminases (e.g., SGOT and SGPT) INFORMATION FOR THE CONSUMER: Since EPIVAL" (divalproex sodium) may produce CNS depression, especially when combined and LDH are frequent and appear to be dose-related. Occasionally, DOSAGE AND ADMINISTRATION: with another CNS depressant (e.g., alcohol), patients should be laboratory tests also show increases in serum bilirubin and abnor­ Epilepsy: EPIVAL0 (divalproex sodium) is administered orally. The advised not to engage in hazardous activities, such as driving a car recommended initial dosage is 15 mg/kg/day, increasing at one mal changes in other liver function tests. These results may reflect or operating dangerous machinery, until it is known that they do not potentially serious hepatotoxicity (see WARNINGS). week intervals by 5 to 10 mg/kg/day until seizures are controlled or become drowsy from the drug. Metabolic: Hyperammonemia (see PRECAUTIONS), hyponatremia side effects preclude further increases. and inappropriate ADH secretion. Hyperglycinemia has been report­ The maximal recommended dosage is 60 mg/kg/day. When the REFERENCES: 1. Dreifuss FE, Langer DH. Side effects of valproate. ed and associated with a fatal outcome in a patient with preexisting total daily dose is 125 mg or greater, it should be given in a divided /4raJWerJ1988;84(suppl1A):34-41. 2. Dean CJ. Valproate. In: non-ketotic hyperglycinemia. regimen (see Table 2). Wyllie E, ed. The Treatment of Epilepsy: Principles and Practices. Genitourinary: Enuresis The frequency of adverse effects (particularly elevated liver Philadelphia, Pa: Lea & Febiger; 1993:chap 77. 3. Wilder BJ, enzymes) may increase with increasing dose. Therefore, the benefit Ramsay RE, Murphy JV, Karas BJ, Marquardt K, Hammond EJ. Pancreatic: There have been reports of acute pancreatitis occurring gained by improved seizure control must be weighed against the Comparison of valproic acid and phenytoin in newly diagnosed in association with therapy with valproic acid. increased incidence of adverse effects. tonic-clonic seizures. Neurology 1983;33:1474-6. 4. Turnbull DM, Howel D, Rawlins MD, Chadwick DW. Which drug for the adult Special Senses: Hearing loss, either reversible or irreversible, has Table 2 epileptic patient: phenytoin or valproate? Br Med J1985;290: been reported; however, a cause and effect relationship has not Initial Doses by Weight (based on 15 mg/kg/day) been established. 815-9. 5. Covanis A, Gupta AK, Jeavons PM. Sodium valproate: Weight Dosage (mg) monotherapy and polytherapy. Epilepsia 1982;23:693-720. Other: Edema of the extremities has been reported. Total Daily equivalent to valproic acid 6. Kakegawa N, Miyakoshi M, Seino M. Monopharmacy by sodium Bipolar Disorder: The incidence of adverse events has been ascer­ kg lb Dose (mg) Dose 1 Dose 2 Dose 3 valproate (SV) and the blood concentration. In: Program and tained based on data from two short-term (21 day) placebo-con­ abstracts of the XI Epilepsy International Symposium; September 10-24.9 22-54.9 250 125 0 125 trolled clinical trials of divalproex sodium in the treatment of acute 30,1979; Firenze, Italy. Abstract: 153. 7. Epival (divalproex sodi­ 55-87.9 mania, and from two long-term (up to 3 years) retrospective open 25-39.9 500 250 0 250 um). Product Monograph. Abbott Laboratories, Limited. 8. Wilder trials. 40-59.9 88-131.9 750 250 250 250 BJ, Rangel RJ. Review of valproate monotherapy in the treatment of 60-74.9 132-164.9 1000 250 250 500 generalized tonic-clonic seizures. Am J/Wetf1988;84(suppl 1A): Most Commonly Observed: During the short-term placebo-con­ 75-89.9 165-197.9 1250 500 250 500 trolled trials, the six most commonly reported adverse events in 7-13. patients (N=89) exposed to divalproex sodium were nausea (22%), As the dosage of divalproex sodium is raised, blood levels of phe­ ABBOTT LABORATORIES. LIMITED headache (21%), somnolence (19%), pain (15%), vomiting (12%), nobarbital and/or phenytoin may be affected (see PRECAUTIONS, P.O.BOX 6150. STATION CENTRE-VILLE and dizziness (12%). under Drug Interactions). a MONTREAL, QUEBEC H3C 3K6 In the long-term retrospective trials (634 patients exposed to dival­ Patients who experience G.I. irritation may benefit from administra­ Product Monograph available on request. _. proex sodium), the six most commonly reported adverse events tion of the drug with food or by a progressive increase of the dose © Abbott Laboratories, Limited ® lpAABl

Downloaded from https://www.cambridge.org/core. IP address: 170.106.35.234, on 27 Sep 2021 at 06:25:02, subject to the Cambridge Core terms of use, available at See ifc. https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0317167100040403 XXI FONDATION BAXTER & ALMA RICARD AND THE UNIVERSITY OF TORONTO AND THE TORONTO HOSPITAL ANNOUNCE THE CHAIR IN CEREBROVASCULAR NEUROSURGERY

A Search Committee has been established to appoint the first holder of the Ricard Chair in Cerebrovascular Neurosurgery at the University of Toronto and The Toronto Hospital. Candidates should have a background in the clinical and research aspects of cerebrovascular neurosurgery and should be eligible for appoint­ ment as a Staff Neurosurgeon at The Toronto Hospital. The appointment will be made effective July 1, 1995. Candidates wishing to be considered by the Search Committee should send a letter of interest to the Chair of the Search Committee whose address is indicated below, by February 28th.

It is expected that this appointment will be made at the Associate Professor or Professor level commensurate with experience and qualifications. In accordance with its Employment Equity Policy, "My husband is 55 years old. And he's been stolen from me." the University of Toronto encourages applications from qualified Alzheimer Disease is a degenerative brain disorder that women and men, members of visible minorities, aboriginal peo­ destroys vital brain cells. It affects over 300,000 Canadians. And that's not including the people who love them. ples and persons with disabilities. Also, in accordance with Slowly, the disease steals away the ability to think, Canadian immigration requirements, this advertisement is directed understand, remember, communicate, or perform the simplest tasks, leaving them completely dependent. to Canadian citizens and permanent residents. There is no known cause, nor is there a cure. Today. The Alzheimer Society of Canada is a national organiza­ tion dedicated to helping those affected by the disease, Charles H. Tator, M.D., F.R.C.S.C. as well as their caregivers. We also conduct research into Chair, Search Committee, Ricard Chair possible causes, treatments and a cure, so that we can put an end to the devastation The Toronto Hospital, Western Division of this killer disease. 399 Bathurst Street, 2-435 McLaughlin Pavilion Tomorrow. Alzheimer Toronto, Ontario M5T 2S8 CANADA HelpforToday. HopeforTomorrow

FELLOWSHIP IN NEUROMUSCULAR DISEASES The Southwestern Ontario Regional Neuromuscular Clinic, Victoria Hospital, University of Western Ontario, will offer one post-clinical training fellowship of 1-2 years duration, combining clinical and electrophysiological ADVERTISERS INDEX experience in the neuromuscular diseases with a signifi­ cant laboratory exposure to basic science research. There Abbott is scope for a number of research projects within estab­ Epival - ifc, xx, xxi lished areas in the department depending on the interests and talents of the applicant. Current research includes Ciba/Geigy clinical and laboratory studies of the immunological Tegretol - obc, xiv, xvi, xvii aspects and immunotherapy of the inflammatory polyneu­ ropathies (animal models), the electrophysiological investi­ Dupont gation of critical illness polyneurophathy and respiratory Sinemet - x, xi function, and studies of the immunology of myasthenia Hoescht gravis, focusing on the thymus and acetylcholine receptor- Frisium - ibc, iii, 82 specific B cells. Parke Davis Address inquiries with a curriculum vitae to: Neurontin - ix, xiii, xviii, xix Dr. A.F. Hahn Syntex Department of Clinical Neurological Sciences Victoria Hospital Ticlid - iv, v, vi, vii 375 South St. Classified Ads London, Ontario, Canada - xv, xxii N6A 4G5 Phone 667-6639 Fax 667-6766 Position to be filled by April 1, 1995, approximate start time July 1, 1995 (flexible depending on candidate).

Downloaded from https://www.cambridge.org/core. IP address: 170.106.35.234, on 27 Sep 2021 at 06:25:02, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0317167100040403 (xxii) Rational therapy with Frisium is a well orchestrated approach to complete seizure control inpatients of all ages, regardless of seizure type. Adverse events with Frisium are generally mild and transient.' Clinically significant drug interactions are uncommon, and impairment of alertness is less pronounced with Frisium than with other benzodiazepines.* Help keep these patients in harmony with their surroundings. Add s Frisiu^H^H A A m(clobazam) To achieve seizure control.

I PAABI FRI 2698/9053E * Please consult precautions statement in Product Monograph. I, Hoechst and ®, Reg. Trademarks of Hoechst AG, Germany Hoechst Canada Inc., Montreal H4R2E8 llOGCIiST For brief prescribing information see page 82. Downloaded from https://www.cambridge.org/core. IP address: 170.106.35.234, on 27 Sep 2021 at 06:25:02, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0317167100040403 ways of telling when a epilepsy patient is on Excellent Seizure Control. Convenient B.I.D. Dosing. BTegretol® CR(controlled-release When initiating or switching therapy, carbamazepine) controls seizures in many consider Tegretol CR. It comes in easy- patients—with little impact on cognitive to-break 200mg and 400mg tablets for function1:2 Tegretol CR can leave many dosage flexibility, and offers B.I.D. dosing patients free to think clearly and do to enhance patient their best.1,2 compliance. Consistent Blood Levels. Tegretol CR delivers fewer "peaks and valleys" in blood levels than conven­ tional Tegretol. That means fewer side effects and a more stable pattern of Helping epilepsy patients reach cognitive functioning.34 their full potential.

PAAB CCPP Downloaded from https://www.cambridge.org/core. IP address: 170.106.35.234, on 27 Sep 2021 at 06:25:02, subject to the CambridgeGeig Corey terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0317167100040403 Mississauga, Ontario L5N 2W5 For brief prescribing information see pages xvi, xvii.