Prescription Drugs

CLINICAL PHARMACOLOGY CYLERT (pemoline) has a pharmacological activity similar to that of other known central nervous system stimulants; however, it has minimal sympathomimetic effects. Although studies indicate that pemoline may act in animals through dopaminergic mechanisms, the exact mechanism and site of action of the drug in man is not known. There is neither specific evidence which clearly establishes the mechanism whereby CYLERT (pemoline) produces its mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system. Pemoline is rapidly absorbed from the gastrointestinal tract, Approximately 50% is bound to plasma proteins. The serum half-life of pemoline is approximately 12 hours. Peak serum levels of the drug occur within 2 to 4 hours after ingestion of a single dose. Multiple dose studies in adults at several dose levels indicate that steady state is reached in approximately 2 to 3 days. In animals given radiolabeled pemoline, the drug was widely and uniformly distributed throughout the tissues, including the brain. Pemoline is metabolized by the liver. Metabolites of pemoline include pemoline conjugate, pemoline dione, mandelic acid, and unidentified polar compounds. CYLERT (pemoline) is excreted primarily by the kidneys with approximately 50% excreted unchanged and only minor fractions present as metabolites. CYLERT (pemoline) has a gradual onset of action. Using the recommended schedule of dosage titration, significant clinical benefit may not be evident until the third or fourth week of drug administration.

Cylert (pemoline) Because of its association with life threatening hepatic failure, CYLERT (pemoline) should not ordinarily be considered as first line drug therapy for ADHD (see INDICATIONS AND USAGE). Since CYLERT (pemoline) ´s marketing in 1975, 13 cases of acute hepatic failure have been reported to the FDA. While the absolute number of reported cases is not large, the rate of reporting ranges from 4 to 17 times the rate expected in the general population. This estimate may be conservative because of under reporting and because the long latency between initiation of CYLERT (pemoline) treatment and the occurrence of hepatic failure may limit recognition of the association. If only a por-tion of actual cases were recognized and reported, the risk could be substantially higher. Of the 13 cases reported as of May 1996, 11 resulted in death or liver transplantation, usually within four weeks of the onset of signs and symptoms of liver failure. The ear-liest onset of hepatic abnormalities occurred six months after initiation of CYLERT (pemoline) . Although some reports described dark urine and nonspecific prodromal symptoms (e.g., anorexia, malaise, and gastrointestinal symp-toms), in other reports it was not clear if any prodromal symptoms preceded the onset of jaundice. It is also not clear if the recom-mended baseline and periodic liver function testing are predictive of these instances of acute liver failure. CYLERT (pemoline) should be dis-continued if clinically significant hepatic dysfunction is observed during its use (see PRECAUTIONS). DESCRIPTION CYLERT (pemoline) is a central nervous system stimulant. Pemoline is structurally dissimilar to the amphetamines and methylphenidate. It is an oxazolidine compound and is chemically identified as 2-amino-S-phenyl-2-oxazolin4-one. Pemoline is a white, tasteless, odorless powder, relatively insoluble (less than 1 mg/mL) in water, chloroform, ether, acetone, and benzene; its solubility in 95% ethyl alcohol is 2.2 mg/mL. CYLERT (pemoline) is supplied as tablets containing 18.75 mg, 37.5 mg or 75 mg of pemoline for oral administration. CYLERT (pemoline) is also available as chewable tablets containing 37.5 mg of pemoline. Inactive Ingredients 18.75 mg tablet: corn starch, gelatin, lactose, magnesium hydroxide, polyethylene glycol and talc. 37.5 mg tablet: corn starch, FD& C Yellow No. 6. gelatin, lactose, magnesium hydroxide, polyethylene glycol and talc. 37.5 mg chewable tablet: corn starch FD& C Yellow No. 6, magnesium hydroxide, magnesium stearate, mannitol, Polyethylene glycol, povidone, talc and artificial flavor. 75 mg tablet: corn starch, gelatin, iron oxide, lactose, magnesium hydroxide, polyethylene glycol and talc.

INDICATIONS CYLERT (pemoline) is indicated in Attention Deficit Hyperactivity Disorder (ADHD). Because of its association with life threatening hepatic failure, CYLERT (pemoline) should not ordinarily be considered as first line therapy for ADHD (see WARNINGS). CYLERT (pemoline) therapy should be proof of a total treatment program which typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in children with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate to severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. The diagnosis of this syndrome should not be made with finality when these symptoms are only of comparatively recent origin. Nonlocalizing (soft) neurological signs, learning disability, and abnormal EEG may or may not be present, and a diagnosis of central nervous system dysfunction may or may not be warranted. DOSAGE AND ADMINISTRATION CYLERT (pemoline) is administered as a single oral dose each morning. The recommended starting dose is 37.5 mg/day. This daily dose should be gradually increased by 18.75 mg at one week intervals until the desired clinical response is obtained. The effective daily dose for most patients will range from 56.25 to 75 mg. The maximum recommended daily dose of pemoline is 112.5 mg. Clinical improvement with CYLERT (pemoline) is gradual. Using the recommended schedule of dosage titration, significant benefit may not be evident until the third or fourth week of drug administration. Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy. HOW SUPPLIED CYLERT (pemoline) is supplied as monogrammed, grooved tablets in three dosage strengths: 18.75 mg tablets (white) in bottles of 100 (NDC 0074-6025-13); 37.5 mg tablets (orange-colored) in bottles of 100 (NDC 0074-6057-13); 75 mg tablets (tan-colored) in bottles of 100 (NDC 0074-6073-13). CYLERT (pemoline) Chewable is supplied as 37.5 mg monogrammed, grooved tablets (orange- colored) in bottles of 100 (NDC 0074-6088-13). Recommended Storage: Store below 86° F (30° C).

PATIENT INFORMATION See WARNINGS, CONTRAINDICATIONS, and PRECAUTIONS.

OVERDOSE Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, hypertension and mydriasis. Consult with a Certified Poison Control Center regarding treatment for up to date guidance and advice. Treatment consists of appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. Gastric contents may be evacuated by gastric lavage. Other measures to detoxify the gut include administration of activated charcoal and a cathartic. Chlorpromazine has been reported in the literature to be useful in decreasing CNS stimulation and sympathomimetic effects. Efficacy of peritoneal dialysis or extracorporeal hemodialysis for CYLERT (pemoline) overdosage has not been established. CONTRAINDICATIONS CYLERT (pemoline) is contraindicated in patients with known hypersensitivity or idiosyncrasy to the drug. CYLERT (pemoline) should not be administered to patients with impaired hepatic function (see ADVERSE REACTIONS).

SIDE EFFECTS The following are adverse reactions in decreasing order of severity within each category associated with CYLERT (pemoline) : Hepatic: There have been reports of hepatic dysfunction, ranging from asymptomatic reversible increases in liver enzymes to hepatitis, jaundice and life- threatening hepatic failure, in patients taking CYLERT (see PRECAUTIONS and WARNINGS). Hematopoietic: There have been isolated reports of aplastic anemia. Central Nervous System: The following CNS effects have been reported with the use of CYLERT (pemoline) : convulsive seizures: literature reports indicate that CYLERT (pemoline) may precipitate attacks of Gilles de la Tourette syndrome; hallucinations; dyskinetic movements of the tongue, lips, face and extremities: abnorrnal oculomotor function including nystagmus and oculogyric crisis; mild depression; dizziness; increased irritability; headache; and drowsiness. Insomnia is the most frequently reported side effect of CYLERT (pemoline) , it usually occurs early in therapy prior to an optimum therapeutic response. In the majority of cases it is transient in nature or responds to a reduction in dosage. Gastrointestinal: Anorexia and weight loss may occur during the first weeks of therapy. In the majority of cases it is transient in nature; weight gain usually resumes within three to six months. Nausea and stomach ache have also been reported. Genitourinary: A case of elevated acid phosphatase in association with prostatic enlargement has been reported in a 63 year old male who was treated with CYLERT (pemoline) for sleepiness. The acid phosphatase normalized with discontinuation of CYLERT (pemoline) and was again elevated with rechallenge. Miscellaneous: Suppression of growth has been reported with the long- term use of stimulants in children. (See WARNINGS.) Skin rash has been reported with CYLERT (pemoline) . Mild adverse reactions appearing early during the course of treatment with CYLERT (pemoline) often remit with continuing therapy. If adverse reactions are of a significant or protracted nature, dosage should be reduced or the drug discontinued. DRUG ABUSE AND DEPENDENCE Controlled Substance: CYLERT (pemoline) is subject to control under DEA schedule IV. Abuse: CYLERT (pemoline) failed to demonstrate a potential for self- administration in primates. However, the pharmacologic similarity of pemoline to other psychostimulants with known dependence liability suggests that psychological and/ or physical dependence might also occur with CYLERT (pemoline) . There have been isolated reports of transient psychotic symptoms occurring in adults following the long- term misuse of excessive oral doses of pemoline. CYLERT (pemoline) should be given with caution to emotionally unstable patients who may increase the dosage on their own initiative. DRUG INTERACTIONS The interaction of CYLERT (pemoline) with other drugs has not been studied in humans. Patients who are receiving CYLERT (pemoline) concurrently with other drugs, especially drugs with CNS activity, should be monitored carefully. Decreased seizure threshold has been reported in patients receiving CYLERT (pemoline) concomitantly with antiepileptic medications.

WARNINGS Because of its association with life threatening hepatic failure, CYLERT (pemoline) should not ordinarily be considered as first line drug therapy for ADHD (see INDICATIONS AND USAGE). Since CYLERT (pemoline) 's marketing in 1975, 13 cases of acute hepatic failure have been reported to the FDA. While the absolute number of reported cases is not large. the rate of reporting ranges from 4 to 17 times the rate expected in the general population. This estimate may be conservative because of under reporting and because the long latency between initiation of CYLERT (pemoline) treatment and the occurrence of hepatic failure may limit recognition of the association. If only a por-tion of actual cases were recognized and reported, the risk could be substantially higher. Of the 13 cases reported as of May 1996, 11 resulted in death or liver transplantation, usually within four weeks of the onset of signs and symptoms of liver failure. The ear-liest onset of hepatic abnormalities occurred six months after initiation of CYLERT (pemoline) . Although some reports described dark urine and nonspecific prodromal symptoms (e.g., anorexia, malaise, and gastrointestinal symp-toms), in other reports it was not clear if any prodromal symptoms preceded the onset of jaundice. It is also not clear if the recom-mended baseline and periodic liver function testing are predictive of these instances of acute liver failure. CYLERT (pemoline) should be dis-continued if clinically significant hepatic dysfunction is observed during its use (see PRECAUTIONS). Decrements in the predicted growth (i.e., weight gain and/or height) rate have been reported with the long- term use of stimulants in children. Therefore, patients requiring long-term therapy should be carefully monitored. PRECAUTIONS General Clinical experience suggests that in psychotic children administration of CYLERT (pemoline) may exacerbate symptoms of behavior disturbance and thought disorder. CYLERT (pemoline) should be administered with caution to patients with significantly impaired renal function. Since CYLERT (pemoline) 's market introduction. there have been reports of elevated liver enzymes associated with its use. Many of these patients had this increase detected several months after starting CYLERT (pemoline) . Most patients were asymptomatic, with the increase in liver enzymes returning to normal after CYLERT (pemoline) was discontinued. Liver function tests should be performed prior to and periodically during therapy with CYLERT (pemoline) . Treatment with CYLERT (pemoline) should be initiated only in individual without liver disease and with normal baseline liver function tests. The relationship, if any, between reversible elevations in liver function tests and the occurrence of life threatening hepatic failure in patients on long-term therapy with CYLERT (pemoline) is not known. Liver function testing may not predict the onset of acute liver failure. Nonetheless, CYLERT (pemoline) should be discontinued if clinically significant liver function test abnormalities are revealed at any time during therapy with this drug (see WARNINGS). Drug Interactions: The interaction of CYLERT (pemoline) with other drugs has not been studied in humans. Patients who are receiving CYLERT (pemoline) concurrently with other drugs, especially drugs with CNS activity, should be monitored carefully. Decreased seizure threshold has been reported in patients receiving CYLERT (pemoline) concomitantly with antiepileptic medications. Carcinogenesis: Long-term studies have been conducted in rats with doses as high as 150 mg/kg/day for eighteen months. There was no significant difference in the incidence of any treated and control animals. neoplasm between Mutagenesis: Data are not available concerning long-term effects on mutagenicity in animals or humans. Impairment of Fertility: The results of studies in which rats were given 18.75 and 37.5 mg/ kg/ day indicated that pemoline did not affect fertility in males or females at those doses. Pregnancy: Teratogenic effects. Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses of 18.75 and 37.5 mg/ kg/ day and have revealed no evidence of impaired fertility or harm to the fetus. There are, however, no adequate and well- controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nonteratogenic effects. Studies in rats have shown an increased incidence of stillbirths and cannibalization when pemoline was administered at a dose of 37.5 mg/kg/day. Postnatal survival of offspring was reduced at doses of 18.75 and 37.5 mg/kg/day. Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when CYLERT (pemoline) is administered to a nursing woman. Pediatric Use: Safety and effectiveness in children below the age of 6 years have not been established. Long-term effects of CYLERT (pemoline) in children have not been established (see WARNINGS CNS stimulants, including pemoline, have been reported to precipitate motor and phonic tics and Tourette's syndrome. Therefore, clinical evaluation for tics and Tourette's syndrome in children and their families should precede use of stimulant medications. Drug treatment is not indicated in all cases of ADHD and should be considered only in light of complete history and evaluation of the child. The decision to prescribe CYLERT (pemoline) should depend on the physician's assessment of the chronicity and severity of the child's symptoms and their appropriateness for his/her age. Prescription should not depend solely on the presence of one or more of the behavioral characteristics.