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Home , Clonidine, Management of depression, Mirtazapine

A Monthly Newsletter for Health Care Professionals Children’s Medical Center at the University of Virginia

Volume 6 Number 2 February 2000

Mirtazapine: Potential advantages in adolescents with associated with chronic illness Marcia L. Buck, Pharm.D., FCCP

any of the newer , has been found in several large -scale M including the selective clinical trials to be a safe and effective inhibitors (SSRIs), have been . In a recent meta -analysis of eight used in the in children clinical trials, mirtazapine was found to be and adolescents. A subset of this population, significantly better than and comparable children with depression associated with chronic to in the treatment of major illness, may require a different approach. depression in adults with symptoms of . 4 Several studies have documented the prevalence Other trials have shown mirtazapine to be of depression in these patients. While the equivalent to or better than , majority of the papers published deal with the , , , , pediatric population, there are also and in the treatment of m oderate to children with depression associated with other severe depression. 1,5,6 chronic, debilitating diseases, such as cystic fibrosis, sickle cell disease, and Crohn's disease. Potential Role in Adolescents Some of these patients may benefi t from the use While currently only approved by the Food and of mirtazapine, a antidepressant with Drug Administration for the treatment of unique properties. depression in patients > 18 years of age, mirtazapine may be very useful in selected Mechanism of Action adolescent patien ts. Although there are now The precise mechanism of action of mirtazapine many safe and effective antidepressants from is still uncertain. In general, the tetracyclic which to chose, mirtazapine offers the additional antidepressants, mirtazapine and , act advantage of stimulating and promoting by i ncreasing central noradrenergic and weight gain. Typically considered adverse serotoneric (5 -HT 1) . The effects in adults with depression, these e ffects methods by which they accomplish these results may be very beneficial in adolescents with differ. Mirtazapine appears to act primarily as a conditions such as Crohn's disease or cystic potent antagonist at postsynaptic 5 -HT 2 and 5 - fibrosis where weight gain is often a challenge HT 3 () and central α2- and in children who are receiving . (noradrenergic) receptors. Maprotiline does not possess this degree of receptor subtype Although no data are currently available in specificity. These differences have led some children, in prema rketing studies enrolling investigators to refer to mirtazapine as the first adults, 17% reported an increase in appetite and noradrenergic and specific serotoneric 12% reported weight gain. In some studies, up to antidepressant (N aSSA). 1,2 5-10% of patients reported a gain of > 7% body weight. 2 At this time, several patients at the Mirtazapine is also a potent antagonist at central Children's Medical Center have been treated with and peripheral (H 1) receptors, which mirtazapine with positive results in terms of both may explain its effects. Unlike weight gain and improvement in depressive maprotiline, mirtazapine has little activity at symptoms. muscarinic or peripheral α1-adrenergic receptors. 1-4 The pharmacokinetic profile of mirtazapine has not been evaluated in children. In studies of adults, the drug is rapidl y and completely Clinical Efficacy absorbed after oral administration. Peak serum concentrations are reached within 2 hours than 1% of patients include: asthenia (8%), following a dose. Absolute of elevations in serum or nonfasting mirtazapine is approximately 50% and is not levels (6 -15%), central nervous affected by the presence of food. Mirtazapine is system disturbances such as abnormal dreams, approxim ately 85% protein bound. 1,2 agitation, anxiety, confusion, or dizziness (1 - 7%), myalgias and flu -like symptoms (2 -5%), Mirtazapine is metabolized primarily through urin ary frequency (2%), edema (1 -2%), tremor demethylation by (CYP) 3A4 (2%), elevations in hepatic (2%), enzymes and by CYP2D6 and pruritus or rash (1%), and (1%). 2,3 CYP1A2. The metabolites then undergo glucuronide conjugation prior to renal Rare, but significant, adverse effects observed elimination. Before conjugation, some of the with mirtazapine include (2 out metabolites possess minor pharmacologic of 2,796 patients in premar keting trials), severe activity. The mean elimination half -life of (1 patient) and (2 patients mirtazapine in adults is 20 to 40 hours. with a previous history of seizures). In these Interestingly, female patients, regardless of age, cases, the patients fully recovered after tend to have a significantly longer half -life than discontinuation of the drug. 1-3 ma les (an average of 37 hours for females versus 26 hours for males). 1-3 Patient Counseling and Monitoring

Drug Interactions  Although agranulocytosis ha s only rarely Because of its through the been reported with mirtazapine, families of cytochrome P450 system, there is the patients receiving the drug should be aware potential for significant drug interactions with of the risk. Parents should understand the mirtazapine. While mirtazapine it self does not need to seek prompt medical attention for appear to function as either an inducer or any sign of infection, including fever, chills, inhibitor of these enzymes, it could be affected a sore throat, or fl u-like symptoms. by other drugs which alter enzyme function. To date, no clinically significant drug interactions  Because of the high incidence of sedation with mirtazapine have been reported, but drugs with mirtazapine, families of adolescents metab olized through these pathways should be who are driving should be counseled about closely monitored. 2 the need to determine the patient's degree of impairment prior to allowing the patient to As with other antidepressants, patients who have operate a vehicle. been receiving inhibitors, (Nardil ),  Patients taking mirtazapine should be (Parnate ), or (Marplan ), should counseled that concomitant use of other be off therapy for at least a two week period , such as prior to starting mirtazapine. Use of the two or , will result in agents simultaneously or in rapid succession may additive sedation and impairment of motor result in hyperthermia, autonomic instability, skills. seizures, or coma. 3  In addition, patients and families should Adverse Effects monitor the patient's degree of weight gain In studies of patients 18 years of age and o lder, while on mirtazapine to ensure that it does approximately 16% discontinued mirtazapine not become excessive. because of adverse effects. The most common adverse effects reported in these patients were Management of Overdose (10.4%) and (1.5%). 1-3 Another advantage of mirtazapine in the adolescent population is the minimal risk of When data from multiple clinical trials for with an overdose. A lthough there is still depression in adults were po oled, the most only limited experience with mirtazapine frequent adverse effects reported with overdoses, all patients reported have experienced mirtazapine were somnolence (54%), dry mouth a full recovery. Signs and symptoms associated (25%), (13%), and the previously with overdosage include sedation, disorientation, mentioned increased appetite (17%) and weight and . At this time, there are no gain (12%). Other reactions reported in more reports of mirtazapine causing other , seizures, or coma. Treatment is supportive. Patient management should include a careful Anaphylaxis to Muromonab -CD3 history to identify a multiple -drug ingestion Muromonab -CD3 (also known as OKT3) is used which might include a more toxic agent. in the induction of immunosuppression following organ transplantation and in the management of Dosing Recommendations steroid -resistant graft rejection. Anaphylactic Mir tazapine is marketed as Remeron  by and anaphylactoid reactions to muromonab -CD3 Organon. It is available in 15, 30, and 45 mg are not uncommon. Anaphylactoid reactions tablets. The 15 and 30 mg tablets are scored for typically present with cytokine release syndrome, dose titration. The recommended starting dose , and a shock -like response. In this for adults is 15 mg per day in a single dose. This report, a 15 year old girl who developed an dose is usually given at bedtime to avoid anaphylactoid reaction following her first dose of excessive daytime sedation. In patients who fail muromonab -CD3 for a renal transplant is to respond, dosage increases may be made every presented. Within 10 minutes of receiving a 10 1 to 2 weeks to a maximum of 45 mg per day. 2 mg IV dose, she complained of shortness of Adolescents may start therapy with the adult breath and . She became profoundly dose, with adjustment based on individual patient hypotensive and developed laryngeal stridor response. requiring intubation and inotropic support. Her condition stabilized during the next 24 hours, but Although there are no specific guidelines for the transplanted was lost because of acute dosage adjustment in patients with moderate to infarction. As expected, there were no anti - severe renal or hepatic dysfunction, drug OKT3 antibodies found in serum collected prior accumulation may occur. Conservative dose to, during, or up to 3 months following the escalation and close monitoring for adverse episode. Berkowitz RJ, Possidente CJ, effects is recommended .3 McPherson BR, et al. Anaphylactoid reaction t o muromonab -CD3 in a pediatric renal transplant Summary patient. Pharmacotherapy 2000;20:100 -4. Mirtazapine may play a unique role in the management of adolescents with depression for ADHD associated with chronic illness. In addition to its Clonidine has been used for the management of established role as an antidepressant, mirtazapine children with attention deficit/hyperactivity may be of use in stimulating the appetite and disorder (ADHD) for approximately ten years. improving weight gain in children at risk for While the exact mechanism of action is excessive . Research in this unknown, clonidine, a centrally acting alpha - population is needed to better define the ideal adrenergic , is believed to reduce dosing range, determine population neuronal firing in the , decreasing pharmacokinetic parameters, and identify any excessive central nervous system stimulation. differences in adverse effects. This brief report covers the basic pharmac ology of clonidine, including toxicologic information, References and the studies conducted in children with 1. Hol m KJ, Markham A. Mirtazapine: a review of its use in ADHD to date. The authors present a well - major depression. Drugs 1999;57:607 -31. balanced discussion of the data, including the 2. Tetracyclic antidepressants. In: Olin BR, ed. Drug Facts and Comparisons. St. Louis: Facts and Comparisons. value of clonidine in children who 2000:900 -3. wish to avoid having to take oral 3. Remeron  product information. Organon . April 1996. during the school day. Chafin CC, Hovinga CA, 4. Fawcett J, Barkin RL. A meta -analysis of eight Phelps SJ. Clonidine in the treatment of randomized, double -blind, controlled clinical trials of mirtazapine for the treatment of patients with major attention -deficit hyperactivity disorder. J depression and symptoms of anxiety. J Clin Pediatr Pharm Pract 1999;4:308 -15. 1998;59:123 -7. 5. van Moffaer t M, de Wilde J, Veerecken A, et al. Mirtazapine is more effective than trazodone: a double -blind Cytochrome P450 3A review controlled study in hospitalized patients with major depression. Int Clin Psychopharmacol 1995;10:3 -9. The cytochrome P450 enzyme system i s 6. Wheatley DP, van Moffaert M, Timmerman L, et al. responsible for the metabolism of numerous Mir tazapine: efficacy and in comparison with drugs and is the site of many drug interactions. fluoxetine in patients with moderate to severe major The 3A subfamily is now recognized as being depressive disorder. J Clin Psychiatry 1998;59:306 -12. one of the largest groups within the P450 Literature Review superfamily. This in -depth article begins with a review of the CYP450 syst em, including aspects 1. An injectable preparation of citrate of genetic variation and the significance of without preservatives (Cafcit ; Roxane) was extrahepatic sites. While the role of CYP3A4 is added to the Formulary. This product is now fairly well defined and is given the most indicated for the treatment of apnea of detail, the authors also present some interesting prematurity in infants. Therapy should be findings about CYP3A5 and CYP3A7. The initiated with a loading dose of 20 mg/kg given remai nder of the article is focused on the intravenously over 30 minutes, followed by a developmental aspects of 3A function and how maintenance dose of 5 mg/kg given over 10 these factors affect drug elimination and drug minut es every 24 hours. interactions in children. The article is well written and extensively referenced, making it an 2. Sodium ferric gluconate (Ferrlecit ; Schein) invaluable resource for those interested in was added to the Formulary, restricted to use in pediatric pharmacology. de Wildt SN, Kearns patients receiving hemodialysis. This product is GL, Leeder JS et al. Cytochrome P450 3A: a parenteral iron complex used with Ontogeny and drug disposition. Clin erythropoietin to increase red cell production. Pharmacokinet 1999;37:485 -505. Sodi um ferric gluconate has been used successfully in some patients who experienced pharmacokinetics severe reactions to iron dextran, although there is During the past decade, there have been a still a significant risk for reactions with this number of st udies published describing the preparation. Pediatric dosing has not been pharmacokinetic profile of methylphenidate. The established. authors of this review provide an overview of these studies, with special attention to the 3. , a c yclooxygenase -2 (COX -2) significant variations in individual response and inhibitor, was added to the Formulary with the problems inherent in our curren t practice of restriction to patients with a previous history of a administering methylphenidate as a racemic gastrointestinal bleed or intolerance of non - mixture of the more potent d -threo - specific non -steroidal anti -inflammatory drugs methylphenidate and less potent l -isomer. (NSAIDs), patients on anticoagulants or high - Kimko HC, Cross JT, Abernethy DR. dose steroid therapy, or in patients with Pharmacokinetics and clinical effectiveness of thrombocytopenia or clotting disorders. methylphenidate. Clin Pharmacokinet 199 9;37:457 -70. 4. The 1999 annual report of the Adverse Drug Reaction Reporting Program was also presented. RSV immune globulin and palivizumab review For more information about this report, please This brief review covers the major studies contact Dr. Anne Hendrick, Dire ctor of Drug conducted to date with therapies to prevent Information Services at 4 -8034. respiratory syncytial virus (RSV). The studies are presented sequentially, with the first section Contributing Editor: Marcia L. Buck, Pharm.D. devoted to early work with RSV immune Editorial Board: Anne E. Hendrick, Pharm.D. globulin. The majority of the review focuses on Michelle W. McCarthy, Pharm.D. palivizumab, the which has Douglas S. Paige, R.Ph. become the drug of choice for RSV prophylaxis. If you have a ny comments or suggestions for The guidelines developed by the American future issues, please contact us at Box 274 -11, Academy of Pediatrics are included, as well a s a UVA Medical Center, Charlottesville, VA 22908 discussion of cost. This is a very nice review for or by phone (804) 982 -0921, fax (804) 982 - students and those not already using these agents 1682, or e -mail to [email protected]. in practice. Robinson RF, Nahata MC. Respiratory syncytial virus (RSV) immune globulin and palivizumab for prevention of RSV infection. Am J Health -Syst Pharm 2000;57:259 -67.

Formulary Update The following actions were taken by the Pharmacy and Therapeutics Committee during their meeting on 1/28/00: