THERAPEUTIC REVIEW OF SYMBYAX (OLANZAPINE AND FLUOXETINE CAPSULES

A M C P Te am Exe rc is e Q1 2 00 6 THERAPEUTIC REVIEW OF SYMBYAX (OLANZAPINE AND FLUOXETINE CAPSULES) FOR THE TREATMENT OF BIPOLAR DEPRESSION FOR PITT STREET HEALTH PLAN P&T COMMITTEE Taofik Brown Agnes Cha Bess Kim John Lee 1 0 0 N o r t h P i t t S t r e e t S u i t e 4 0 0 • A l e x a n d r i a , VA 2 2 3 1 4 • 8 0 0 . 8 2 7 . 2 6 2 7 • w w w. a m c p . o r g Table of Contents Evaluation of the Quality of the Dossier Analysis of Therapeutic Value of SYMBYAX Pharmacogenomic Treatment Monograph ISSUES FOR CONSIDERATION BY THE FORMULARY COMMITTEE INDICATIONS PHARMACOKINETICS ADVERSE EFFECTS ALLERGIES AND INTERACTIONS AVAILABILITY AND DOSING THERAPEUTIC EFFICACY SUMMARY OF PHARMACOECONOMIC STUDIES SUMMARY AND RECOMMENDATION 1 4 8 10 12 13 13 13 14 15 16 16 20 21 22 22 23 34 T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n Appendix A - Economic Evaluation of SYMBYAX Budget Analysis of SYMBYAX Decision Analysis of SYMBYAX Appendix B - REFERENCES B r o w n , C h a , K i m a n d L e e i B r o w n , C h a , K i m a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n ii Evaluation of the Quality of the Dossier In response to Pitt Street Health Plan’s submitted unsolicited request, Eli Lilly has responded appropriately with their dossier of SYMBYAX (olanzapine and fluoxetine HCL) for the treatment of bipolar depression. The manufacturer has submitted “product information,” “place of product in therapy,” “modeling report,” as per instructed, and has also supplied adequate information on product description. However, some key details and points have not been addressed in the supplied dossier according to the Academy of Managed Care Pharmacy’s Format for Formulary Submission v 2.0 (2002) that have prevented comprehensive analysis. Initially this report shall review systemic observations prior to specific variances from the AMCP’s Format. Systemic failures seems to center around proper citation and data presentation. The modus operandi is not clearly defined for bipolar depression. Therefore the causes of bipolar depression and effects of SYMBYAX offered by the manufacture are at best educated guesses. Some animal studies are referred to as evidence to support the benefits of SYMBYAX but lack any citation for review, and therefore remain unverified [Page 5, et. al.]. Tendency throughout the dossier provided by the manufacture seems to repeatedly refer to a study as support yet citations are absent or not properly completed for that study. For example, the redundant improperly referenced [1] that was included at every subtitle heading but was not specific as to which page in the prescribing information for SYMBYAX they were referring to, inhibited the process of an efficient in-depth analysis. Another mentionable is the “FDA approved and other studied indication” section was incomplete at best. The AMCP guidelines call for a “detailed discussion” but only one line of text was submitted. The date of FDA approval (January 10th, 2004) was also not included but required. Off label uses were also not included in the text, but olanzapine and fluoxetene individually have off label uses. The question remains if prescribed together as SYMBYAX would they have the same off-label treatments. Weight gain and somnolence are significant adverse effects that may influence discontinuation of treatment. There are atypical antipsychotic agents or other mood stabilizers such as B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 1 Lithium, Lamotrigine, and Quetiapine that offer a more favorable side effect profile to be considered. These drugs may be alternatives to consider once there is more literature to support the use of these specific agents and other atypical psychotics in the future. The manufacturer however either did not deem these drugs as alternatives to SYMBYAX or failed to include them as alternatives. In either case an updated dossier should mention these agents with comparative evidence. Data was inconsistently presented in the provided dossier to Pitt Street Health Plan’s under some points and incorrectly presented if at all with other points. Data was requested in tabular form for section 1.2 but was presented as a list. No attempt was made by the manufacture to generalize findings to Pitt Street Health Plan’s demographic. Alternative treatments were also not considered, claiming that SYMBYAX is the only FDA approved drug for bipolar depress and should be used as a first line in defense. The P&T committee feels that this claim alone does not warrant the utilization of SYMBYAX as the first line of drugs for bipolar depression without additional treatment options. The pharmacokinetics data of the SYMBYAX as well as its constituents are thoroughly described. However, only steady state information for olanzapine (one week) but not for fluoxetine (about 2 months). Fluoxetine requires a much longer time to reach steady state, and may need longer clinical trials to study its total effect on the body. Some sections of the dossier were not provided according to AMCP Format 2.0. Sections 2.3 Clinical and disease management intervention strategies and most if not all of section 2.4 Outcomes studies and economic evaluation supporting were absent. The provided dossier lacks the consistent depth that would provide a proper basis for critical appraisal of SYMBYAX. Perhaps this is due to the nature of SYMBYAX and the disease it is indicated for. The manufacturer has included a budget impact modeling report. No attempt was made to specify the model to Pitts Street Health Plans’ demographic but only generic data was given and the burden of assessment was placed on the P&T committee. Although an interactive Windows based software model was provided. No similar program was provided for the Macintosh or Linux platform. Data inputs for the model structure were provided for, but the preferred results/ B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 2 output model is preferred. Also clinical trials only were 8 weeks in length, but the model’s horizon is one year of treatment. Sensitivity analysis of all variables in a tornado diagram format was also not given. A tabular format should have also been employed to display total resources, utilization, total costs, total effectiveness and increment costs. A section including product value and overall cost was also not included in the provided dossier. The dossier lacked a professional consistency throughout because some sections account for each active ingredient separately, because the included studies weren’t conducted with SYMBYAX as a combination. The dossier was very thorough with the pharmacokinetic and pharmacodynamic portion. It went into depth with the absorption, distribution, and metabolism of olanzapine and fluoxetine. The dossier contained adequate warnings/precautions and possible adverse effects, especially stressing the black box label warning. There were several listings of various interactions with OFC, most of which had suggestions on how to avoid them. However, while the dossier stresses that SYMBYAX is the only FDA approved drug for bipolar depression, the product information was lacking the date of FDA approval. It also did not include information on concomitant therapies, nor a tabular comparison with the PK/PD profiles of other therapeutic agents. Overall the modeling report provided by the dossier was not adequate enough to project health consequences for Pitts Street’s formulary change. Although some of treatment guidelines provided were met, the manufacturer did not provide alternate treatment options. This raises questions about the significance and the overall validity of the entirety of the dossier, especially since all supporting information for formulary inclusion was obtained solely from two improperly cited clinical trials. In addition, the costs of other medical resources were not mention. Although the dossier summarized and conveyed the value of SYMBYAX well, it lacks the breadth of clinical data and understanding required for placement on a formulary. The outcomes of clinical trials which leads to the conclusion of the manufacture to place SYMBYAX as the first line treatment on the formulary requires further data. B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 3 Analysis of Therapeutic Value of SYMBYAX Eli Lilly claims that SYMBYAX’s unchallenged FDA approval to fight bipolar depression warrants first line therapy status and formulary approval. The clinical and economic data presented for SYMBYAX claims significantly better outcomes than olanzapine monotherapy or placebo at a minimal additional cost. However, some aspects of the dossier raise concerns that need to be addressed. The clinical information presented beneficial effects from two unnamed individually randomized, double blind, placebo controlled, multi-national trials. These studies show a significant improvement in MADRS scores, length of depressive episodes, and CGI-BP-Severity of Depression, but less then significant improvement in HAM-A scores. The data was clearly presented in tables for each of these parameters along with statistical significance (p-values). However, long-term outcomes were not addressed outside of a six-month open-label extension phase. Due to the complexity of the disease, the known issues of extended uses of antipsychotic and 2 month requirement for fluoxetine to reach steady state, consideration of SYMBYAX’s effect during a longer period of time should be addressed. Also, no alternate therapies were presented in the dossier for bipolar depression like Lamotrigine, Lithium, Quetiapine or off label Topomax. According to the dossier, approval of SYMBYAX is an economically sound decision to the health plan. However, the economic model utilized in the dossier was not recommended and a different model should be employed as recommended by the AMCP Format. The included budget impact model did not clearly display the process to obtain the final results or conclusions, but only equations were given. Cost effectiveness studies to support SYMBYAX was also absent from the dossier and a tornado diagram was not employed for the sensitivity analysis. The budget impact model used is driven by the various factors such as bipolar depression epidemiology, medication unit cost, dosage, and medication utilization (factors displayed in the equations provided). However, there are limitations of this solely economic model where the effectiveness of the drug can not be accurately measured within the population and only the direct cost of care for bipolar B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 4 depression patients are considered and not the indirect costs due to reduced productivity, unemployment, cost of treatment due to side effects or new drug utilization. Everyone within the plan is affected by the impact of the drug onto the formulary but the manufacturer failed to clarify it. In the determined PMPM (post and) PMPM (pre), the manufacturer did not indicate that they used the entire population within plan (1 million people) instead of the Bipolar depressed patients (BDP). Their values of PMPM (post) and PMPM (pre) are $. $0.1619 and $0.0159 prospectively, instead of the actual BDP value, which would produce different higher inflated values. In addition, there was a lack of consistency stating the actual economic value of SYMBYAX in one section. Annual cost was different from the values of the PMPM and PTMPM from the budget impact ($4.045, 0.003) was different the values of page 68 ($6.064, $0.005). The remaining economic information and calculations provided in the dossier is correct and accurate mathematically. The cost effective analysis of comparing SYMBYAX to other bipolar medications such as Quetiapine, Lamitrogine and Olanzapine, would have painted of better picture of the real world since it distinguishes direct and indirect costs patient and the employer may incur with SYMBYAX. In addition, a sensitivity analysis determined is unclear and could provide more information about alternative assumptions or uncertainty of SYMBYAX, if conditions or situations, such as price adverse events, and were to changes relating to bipolar depression. From a cost effective analysis and cost utility analysis standpoint of view, we agree with the manufacturer, that SYMBYAX is cheaper and has a higher remission rate for bipolar depression than its competitors. However concerns would be raised against SYMBYAX since it contains Olanzapine at a lower dose and the adverse events of SYMBYAX patients may experience similar to Olanzapine. There would be concerns about be compliance to the medication in particularly relating to weight gain, somnolence, and diabetes which can affect values of the drug long term for treatment. In reviewing the dossier, several questions concerning the presented clinical evidence were raised. The FDA has not approved olanzapine for bipolar depression and its use in studies remains unclear. No mention of studies concerning compliance and imB r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 5 provements of SYMBYAX over olanzapine or fluoxetine. Although a plethora of evidence exists for SYMBYAX s effectiveness, convincing data is absent for why combination effectiveness of fluoxetine was beneficial. Fluoxetine monotherapy was not considered in the study, but would provide a baseline for comparison. However, the manufacturer did provide data about improvements on quality of life and working functions in patients treated with SYMBYAX compare to placebo and olanzapine. Some key studies that should be considered in the dossier: 1. Callaghan JT, Bt Bergstrom RF, Ptak LR, et al. Olazapine: Pharmacokinetics and pharmacodynamic profile. Clin Pharmacokinetic. 1999; 37(3):177-93. 2. Seager, M. A. (2005). Chronic coadministration of olanzapine and fluoxetine activates locus coeruleus neurons in rats: implications for bipolar disorder. Pharmacology, 181, 126-133. 3. Maragnoli, M.E. (2004). Fluoxetine and olanzapine have synergistic effects in the modulation of fibroblast growth factor 2 expression within the rat brain. Biological Psychiatry, 55, 1095-1102 4. Manning J.S. Burden illness in Bipolar Depression. Prime care companion J Clin Psychiary 2005; 7(6) 5. Goldsmith DR, Wagstaff AJ, Ibbotson T, Perry CM. Spotlight on lamotrigine in bipolar disorder 6. Ghaemi SN, Hsu DJ, Soldani F, Goodwin FK. Antidepressant in bipolr disorder: the case of caution. 7. Gao K and Calabrese J. Newer treatment studies for bipolar depression. 8. Fu, AZ, Krishman A.N, Harris S.D. Thompson TR. The economic burden of bipolar –related phases of depression versus mania. Drug Benefits Trends 16(11): 569-575,2004. http://www.medscape.com/viewarticles 9. Sachs GS. Unmet Clinical Needs in Bipolar Disorder. Journal of Clinical Psychopharmacology.2003; Vol. 23 Supp1 pg 1-7. The evidence in clinical trials of SYMBYAX may be valid and useful, but due to the lack of information of alternate drug therapies, accurate review of SYMBYAX’s. The lack of transparency in the economic models also has hindered a through review. Because of these reasons, SYMBYAX’s role as a first line agent strictly from the dossier is difficult at best to determine. Overall the results used may be promising in terms of the impact of SYMBYAX in the market, but it is a one-sided analysis that does not provide an accurate picture of factors affecting cost relating it to reality. B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 6 Supporting figures Graph 1 shows that SYMBYAX is more cost effective and can provide higher quality life years that its competitor for bipolar depression. Graph 2 shows that SYMBYAX has a higher chance of adverse events than its competitors for treatment B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 7 Pharmacogenomic Version 2.1 of the AMCP Format requires pharmacogenomic tests for further evidence and analysis. Although this may not be necessary for all products, pharmacogenomic tests should be included in a revised SYMBYAX dossier. According to DiPiro, the disease state of bipolar disorder is shown to have a genetic component. Approximately 80-90% of patients diagnosed with bipolar disorder have a biologic relative with some sort of mood disorder. Monozygotic twin studies also support the genetic theory with concordance rate ranges from 78-80%. In addition, linkage studies have been conducted that suggest that the genetic susceptibility of bipolar disorder may involve loci on chromosomes 4, 6, 12, 18, 21, 22, and X. Because of the impact that genetic factors have on the disorder, pharmacogenetic tests will provide more evidence for SYMBYAX utilization, which can only strengthen Eli Lilly’s position. It is to the manufacturer’s benefit to incorporate pharmacogentic data in a revised dossier for SYMBYAX. Development of a screening process will provide improved clinical identification of a target population. Pharmacogenetic tests for SYMBYAX should be added because they will provide analytic validity and accuracy with a particular genetic characteristic involved with bipolar disorder. These tests may also provide information between the genetic variant and expected clinical outcomes within a target population, thus assessing clinical validity and utility. The addition of these genetic tests is essential to measure the effectiveness and safety in utilizing SYMBYAX when compared to trials of the drug without genetic testing. Using pharmacogenetic testing may determine a population with a higher prevalence of therapeutic efficacy, improving outB r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 8 comes in these patient populations, yet preventing ineffective treatment and added suffering in potentially misdiagnosed patients. Pharmacogenomic tests would further benefit the SYMBYAX dossier by determining differences in drug use costs and clinical outcomes between pharmacogenomic tested populations and usual care populations. B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 9 Treatment SYMBYAX is available in four different strengths: 6/25mg, 12/25mg, 6/50mg, and 12/50mg of Olanzapine and Fluoxetine respectively from two different drug classes. When two drugs are paired to make one single combination drug, it allows for increased compliance and reduced costs. A bipolar depression patient who needs to takes less number of drugs will be able to take drugs properly. Combining the two, FDA approved olanzapine and generic fluoxetine, will also save manufacturing costs by reducing the cost of introducing a new drug entity. For manufactures, introducing SYMBYAX will increase their drug’s patent life and prevent more generics from entering which adds to their profit margin. Since the cost for clinical trials and research for each component of SYMBYAX have already been approved through clinical trials, there is less work and costs for future trials and meta-analyses. The combination, Olanzapine and Fluoxetine are identified to have synergistic effect as seen in different clinical studies which show a rapid response in the decrease of bipolar depression. In addition to some clinical and financial advantages, many disadvantages exist in response to counter the affirmatives. When a patient takes in multiple drugs, there is a greater risk of drug interactions and side effect. Olanzapine, an antipsychotic drug is associated with adverse effects such as weight gain, hyperlipidemia, and diabetes which limit those who should take SYMBYAX as a treatment option. SYMBYAX has an inflexible dose ratios and a limited dosing combination often leads to limited dosing applications. Because of the fixed dose, SYMBYAX would not be appropriate for titrating and because bipolar disorder is extremely unique to every patient, the fixed doses may not be ideal for individual cases. SYMBYAX received FDA approval based on an eight week clinical trial study and so it B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 10 is limited to only a very short term use. So, the physicians who elect to use SYMBYAX need periodic reevaluation for each patient. Current literature on the disease state advises against long-term antidepressant use but recommends that the medication is tapered off after six to twelve months because of the possibility of destabilizing cycles and so SYMBYAX again would not be able to circumvent this issue. However, SYMBYAX is currently being tested for long term use so there is a possibility for preventing depressive and manic relapses. Some argue that combining two medications can result in possible alterations of pharmacokinetics, however, with SYMBYAX, pharmacokinetic profiles are not affected by the presence of the other active ingredient. The different combinations of SYMBYAX decreases olanzapine clearance by 14-16%, thus increasing the AUC, mean max concentration and bioavailability slightly. This small decrease in clearance is attributed to fluoxetine inhibition of CYP2D6, a member of the metabolic pathway for Olanzapine. However, the decrease in clearance is not clinically significant because the metabolic pathway via CYP2D6 is very minor and the pharmacokinetic characteristics of the two components will determine SYMBYAX metabolism. The half-life and time to steady state for both components are not altered. Another prominent affect due to pharmacokinetics is that if SYMBYAX needs to be discontinued because of mania or a toxic event, it will take up to sixteen days for the active ingredient in Fluoxetine to be cleared from the body. The trials for SYMBYAX did not include pharmacokinetic studies for special populations such as those who are pregnant, smokers, race as well as the combined effect with gender. B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 11 Monograph B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 12 Pitt Street Health Plan FORMULARY MONOGRAPH Olanzapine and Fluoxetine HCl (SYMBYAX) Eli Lilly and Company Therapeutic Use: Similar Drugs: Treatment of depressive episodes related to bipolar disorder Olanzapine, Lithium, Lamotrogine, Quetiapine ISSUES FOR CONSIDERATION BY THE FORMULARY COMMITTEE If Olanzapine and Fluoxetine HCl combination can be declared to be therapeutically equivalent or superior to Olanzapine monotherapy, Lithium, Lamotrogine, and Quetiapine, is the addition of SYMBYAX to the formulary justified by its efficacy and financially? INDICATIONS FDA-approved indications: SYMBYAX is indicated for the treatment of depressive episodes associated with Bipolar Disorder. The efficacy of SYMBYAX for long term maintenance therapy has not been established. Off-label uses: None CLINICAL PHARMACOLOGY The exact mechanism of SYMBYAX is unknown, but it has been proposed that the activation of neural systems of serotonin, norepinephrine, and dopamine is responsible for the enhanced antidepressant effect. The synergistic effect of the combination drug has been shown by rat studies. In one study, mRNA levels of fibroblast growth factor 2 (FGF-2), which is found to stimulate neurogenesis for antidepressant therapy, were upregulated in the prefrontal cortex only when the two drugs were coadministered. Another study showed that SYMBYAX increased the rate of firing and burst firing of locus coeruleus neurons, which innervates the prefrontal cortex extensively. These studies support the use of combination SYMBYAX producing a synergistic increase of norepinephrine, dopamine, and serotonin in the prefrontal cortex. PHARMACOKINETICS Route of Administraion: • Oral Absorption: • Absorption and bioavailability of both olanzapine and fluoxetine are not affected by food. Thus, it is unlikely that food would have an effect on SYMBYAX. T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n B r o w n , C h a , K i m , a n d L e e 13 Time to Peak: Following a single dose of 12/25mg SYMBYAX, peak plasma concentrations of olanzapine and fluoxetine occur around 4-6 hours. Metabolism: • The complicated metabolism pathway of fluoxetine via CYP2D6 may lead to drug interactions and potentially affect the use of SYMBYAX. • Olanzapine is extensively metabolized, producing inactive metabolites. Elimination: • Primary route of elimination of fluoxetine is hepatic metabolism to inactive metabolites excreted by the kidney. • The slow elimination of fluoxetine and its active metabolite may lead to accumulation. The steady state concentration after prolonged dosing may last for 4-5 weeks. • After fluoxetine is stopped, the active drug may last for weeks and should be considered when prescribing drugs even after discontinuation. Half Life: • Fluoxetine: acute administration 1-3 days • Fluoxetine: chronic administration 4-6 days • Active metabolite, norfluoxetine: 4-16 days • Olanzapine: 21-54 hours; mean of 30 hours • ADVERSE EFFECTS Summary: SYMBYAX was found to be tolerated as well as olanzapine and fluoxetine are separately. The most common adverse effects associated with SYMBYAX treatment were somnolence, weight gain, increased appetite, asthenia, peripheral edema, tremor, pharyngitis, abnormal thinking and/or motor skills due to CNS activity. Other reported adverse effects include hyperglycemia and diabetes mellitus due to the atypical antypsychotic, orthostatic hypotension, tardive dyskinesia, and increased incidence of cerebrovascular events in elderly patients. Some adverse effects have also been reported when discontinuing SYMBYAX. These include dysphoric mood, irritability, agitation, dizziness, sensory disturbances, insomnia, headache, and hypomania. Although these events are mostly self-limiting, a gradual titration in the dose versus abrupt discontinuation is recommended when possible. [WARNING]: Antidepressants may increase the risk of suicidal thinking and behavior in children and adolescents with major depressive disorder and other psychiatric disorders. Anyone considering the use of SYMBYAX should be closely observed for worsening or changes in behavior. SYMBYAX is not approved for use in pediatric patients. In addition, elderly patients with dementia-related psychosis treated with atypical antipsychotics are at an increased risk of death (mostly cardiovascular or infections). SYMBYAX is not approved for use in treatment of patients with dementia-related psychosis. Monitoring: • • • • • Clinical worsening, suicidality, and unusual behavior changes, especially during the first few months of treatment or dosage changes Symptoms of mania or hypomania History of diabetes and fasting blood glucose levels prior to and throughout the course of therapy Significant weight gain Signs and symptoms of tardive dyskinesia: involuntary dyskinetic movement T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n B r o w n , C h a , K i m , a n d L e e 14 ALLERGIES AND INTERACTIONS Allergies: Premarketing controlled clinical trials indicate SYMBYAX treated patients [4.6% (26/571)] compared to that of placebo [5.2% (25/477)] were similar. Although the majority of rashes appeared were mild, SYMBYAX should be discontinued upon the appearance of rash or of other possible allergic phenomena for which an alternative etiology cannot be identified. Drug Interactions: SYMBYAX should not be used in combination with the following: • MAOI (monoamine oxidase inhibitors) When fluoxetine and MAOI were used in combination, there have been reports of fatal reactions including hyperthermia, rigidity, autonomic instability, and mental status changes. The two drugs should not be used concomitantly, or a minimum of 14 days of discontinued therapy with an MAOI before starting SYMBYAX treatment, or a minimum of 5 weeks of discontinued therapy with SYMBYAX before starting an MAOI. • Thioridazine Fluoxetine may inhibit the 2D6 metabolism of thioridazine, resulting in elevated plasma levels of thioridazine. This may increase the risk of prolonged QT intervals, which may lead to ventricular arrhythmias such as torsades de pointes and sudden death. Thioridazine should not be administered within a minimum of 5 weeks after discontinued SYMBYAX treatment. • Another form of fluoxetine (i.e. Prozac, Prozac Weekly, Sarafem) or olanzapine (Zyprexa, Zyprexa Zydis) Concomitant medication of the same active ingredients may result in a possible overdose of therapy and should be exercised with caution when prescribing. • Drugs that interfere with hemostasis (NSAIDs, aspirin, warfarin, etc.) Concurrent use with SYMBYAX may increase the risk of bleeding. B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 15 AVAILABILITY AND DOSING Available Products: SYMBYAX is available in strengths of 6/25, 6/50, 12/25, and 12/50mg (mg equivalent olanzapine/ mg equivalent fluoxetine). Dosing: Adults: SYMBYAX should be administered orally once daily in the evening, generally beginning with the 6mg/25mg capsule. Dosage adjustments can be made according to efficacy and tolerability. Special Populations: Patients who have a predisposition to hypotensive reactions, hepatic impairment, or factors that may slow down SYMBYAX metabolism (female gender, geriatric age, nonsmoking) should start with the lowest dose of 6 mg/25 mg. No dosage adjustment is required for patients with renal impairment. SYMBYAX has not been studied nor approved for pediatric (<18 y/o) use. SYMBYAX is also not approved for patients with dementia-related psychosis and has not been studied for geriatric (>65 y/o) use. THERAPEUTIC EFFICACY See Evidence table, next page Compared to olanzapine monotherapy and placebo, SYMBYAX significantly lowered MADRS, LOCF, CGI-BP and HAM-A scores, indicating a superior antidepressive effect in bipolar patients1. SYMBYAX also demonstrated a higher rate of response and a shorter onset of response. In addition, remission rates were significantly increased.3 Further secondary analysis studies have shown greater improvements in 5 of 8 components of SF-36, including general health, mental health, social functioning and overall treatment effect when using SYMBYAX.4 Higher rates of nausea and diarrhea were seen in patients using SYMBYAX, but other signs of adverse effects were similar with no added concerns of SYMBYAX inducing mania.3 Quetiapine also showed significant improvement and tolerability in MADRS total scores. 2 SYMBYAX is FDA indicated as a 1st line treatment for bipolar depression because of the synergistic effects Olanzapine and Fluoxetine have on each other. Animal studies have demonstrated clearly that when administered together, there is a significant increase in FGF-2 mRNA levels in important brain regions such as the frontal cortex, enhancing synaptic remodeling and plasticity useful for antidepressant therapy5. An important synergistic effect of the combination is the significant higher firing rate of neurotransmitters in the locus coeruleus, which leads to a decrease in symptoms of bipolar depression6. B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 16 B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 17 B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 18 B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 19 SUMMARY OF PHARMACOECONOMIC STUDIES SUMMARY OF PHARMACOECONOMIC STUDIES In the dossier provided by the manufacturer, they used a budget impact analysis which indicates that increase pharmacy expenditure will be at a minimum through the introduction of SYMBYAX into formulary will have an budget impact that is neutral or unbiased. The utilization of SYMBYAX over other treatments may be more favorable if was done through a cost effective analysis rather than a budget impact model. The budget impact model is driven by the bipolar depression epidemiology, medication unit cost and dosage and medication utilization. However, there are limitations of this economic model where the effectiveness of the drug is not accurately measured and only the direct cost of care for bipolar depression patients is only considered and not the indirect costs reduced productivity, unemployment, cost of treatment due to side effects or new drug utilization. The cost effectiveness of SYMBYAX in comparison to other forms treatments, such as placebo, olanzapine 10mg/day to SYMBYAX 6/25mg in the study, is not referenced by the Eli Lilly. This would have further augmented or strengthen SYMBYAX onto various health plan formularies. In addition, other treatments such as non pharmacologic therapy are known to further reduce outpatient and inpatient costs and improve quality of life and clinical outcomes in some pharmacoeconomic studies. SYMBYAX may have a very small increase budget impact but a cost effectiveness analysis is needed to evaluate as well when compared to other forms of drug treatments to SYMBYAX. The budget impact model used definitely demonstrated that SYMBYAX generate a small difference between post and pre PMPM of $0.003 when distributed over a larger population of members in the health plan, however, other factors such as its effects and non-pharmacologic effects compared to it costs will remain ambiguous. BUDGET IMPACT/COST-EFFECTIVENESS MODELING: The corresponding model used was a budget impact model which was developed in order to explore costs as they related to Pitt Street Health Plan. The model requires inputs of an enrolled member health demographic which receives information of patient lives, age distribution and gender distribution. The estimation process of the model parameters is the bipolar depression epidemiology, medication unit cost and dosage and medication utilization drives the model parameter. The inputs are translated into the budget analysis of SYMBYAX. The estimated total difference PMPM before and after placing SYMBYAX on formulary is $0.003 and the estimated total difference between PTMPM before and PTMPM after the addition of SYMBYAX onto formulary is $4.047. All analysis is based on estimates and assumptions of SYMBYAX before and after medication costs. A sensitivity analyses was unclear in the dossier in regarding to impact of the worse case and best case scenario in regarding SYMBYAX to other drugs in the same market. In regarding to impact of the formulary addition of SYMBYAX, it showed to have a large budget impact of $705, 918.00, which is the difference between before and after the addition of SYMBYAX onto the formulary. The difference in PMPM before and PMPM after ($1.193 and $1.215) is $0.023. This shows a huge increase budget impact on the pharmacy formulary which could be related to the increase of number of lives that was covered in the plan, decrease in percentage of patient within the range of 18-65, and increase of younger than 18 years of age. The budget impact of SYMBYAX onto the Pitt Street formulary with patients 18-65 years at 61% shows a drop in budget impact. This would make the introduction of the drug to be expensive from a one sided point of view because uncertainty factors and direct costs. But cost effective analysis point of view, it may be very cost efficient if considering direct, indirect costs, intangible costs and nonpharmacological therapy are being measured appropriately. B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 20 SUMMARY AND RECOMMENDATION Upon extensive review of SYMBYAX and alternate treatments for Bipolar Depression, we have concluded that SYMBYAX is therapeutically effective as well as cost effective. SYMBYAX significantly lowers MADRS, LOCF, CGI-BP and HAM-A scores, indicating a superior antidepressive effect in bipolar patients compared to placebo. This is due to the synergistic effects Olanzapine and Fluoxetine have on each other. SYMBYAX also demonstrates high rates of response and remission, as well as a short onset of response. Patients have experienced improvements in general health, mental health, social functioning and overall treatment effect when using SYMBYAX. Regarding the impact of Pitt Street Health Plan formulary addition of SYMBYAX, it shown to have a large budget impact of $705, 918.00, which is the difference between before and after the addition of SYMBYAX onto the formulary. (See appendix A for full details.) The difference in PMPM before and PMPM after ($1.193 and $1.215) is $0.023. However, from a cost effective analysis point of view, it may be very cost efficient if considering direct, indirect costs, intangible costs and non-pharmacological therapy are being measured appropriately. Our decision tree analysis also considered compliance to therapy as well as observed provider costs associated with these therapies in a bipolar disorder population. According to our analysis, SYMBYAX is in favor over Quetiapine, Lamitrogine, Olanzapine because it has the least cost but the most benefits in terms of efficacy of adjusting the quality of life of patients. In conclusion, we have determined that based on the incremental cost effectiveness ratio, cost of cost utility analysis, and comparing the remission rates, SYMBYAX would be more cost effective in treating bipolar depression and it should be placed on the formulary from an economic standpoint. Clinical evidence has proven SYMBYAX to be clinically effective in treating bipolar depression, and is strongly suggested in the recent Texas Treatment Algorithm. However, there is an inadequate amount of clinical data that proves SYMBYAX to have improved efficacy compared to alternative treatments. Therefore, we recommend placing SYMBYAX on the formulary as second line treatment, requiring a prior authorization from a physician. In addition, patients are required to try at least 2 months of first line treatment Quetiapine for bipolar depression before initiating SYMBYAX. Although SYMBYAX is more cost effective, this formulary process is suggested to take place until further clinical studies provide evidence that SYMBYAX is more efficacious than alternative treatments. MONOGRAPH PREPARED BY: Taofik Brown, Agnes Cha, Bess Kim, and John Lee REFERENCES - see Appendix B B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 21 Appendix A - Economic Evaluation of SYMBYAX Budget Analysis of SYMBYAX Budget Impact = Total medication Cost (post)- Total medication Cost (Pre) $1.94 million -$1.91 million = 0.03 million or $30,000.00 PMPM = (Total Medication Cost (post)/BDP)/12 BDP= Lives * Percentage (18-65)* Σ (gender)*Prevalence (gender) BDP (women) = 1MM * 62%* 54%*0.17% = 575.484 BDP (men) = 1MM * 62%* 45.4%*0.11% = 309.628 Total BDP = 575.484 + 309.628 Total BDP = 885.112 PMPM (post) = {($1942986/1.MM)/12} = $. 0.1619 PMPM (pre) = {($1906819/1.MM)/12} = $ 0.1589 Difference in PMPM (post)-PMPM (pre) = 0.1619-0.1589 = 0.002998 ~ 0.0030 DTP = Dx treatment rate *BDP DTP = 84/100* 885.112 = 743.50 PTMPM (post) = {Total Medication post/DTP} /12 PTMPM (post) = {1942986/ 743.50}/12 = 217.77 PTMPM (pre) = {1906819/ 743.50}/12 = 213.72 Difference between PTMPM (post – pre)= $217.77-213.72 = $4.054 Their calculations seem to be accurate except that they used the entire population in plan to find the values of PMPM (post) and PMPM (pre), which are $. $0.1619 and $0.0159 prospectively, instead of the actual BDP value, which would produce different higher inflated values. B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 22 Decision Analysis of SYMBYAX We decided to use a cost of illness, cost effectiveness analysis and cost utility analysis to observe the effectiveness of SYMBYAX compared to other forms of treatment to reduce remission rate and be compliant to therapy as well as to observe provider costs associated with these therapies in a bipolar disorder population. The primary endpoints of both analyses are total cost in dollars per person. The primary CUA primary endpoint was the improvement of life in terms of quality adjusted life year (QALY), which reflects a decrease quality of life such as side effects, medical treatments, complications, and relapse to bipolar depression. Cost of Illness Direct Costs Total Costs estimated (Indirect cost + Direct Costs) Cost range of bipolar patient is from Estimated Mean treatment cost if get side effects.2 Estimated treatment cost if there is relapse.1 = $22,931 /per patient =$11,276 - $672,789 /patient/year.21 =$1850.00 = $5503.00 These estimated cost of illness for bipolar disorder/depression are from various studies.1,2,3 B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 23 Cost Utility Analysis We used a utility rating scale similar to various clinical studies used to assess the following parameters that shows the probability value score of an adverse reaction from clinical studies these drug treatments as well as obtaining Score are ranged from 0 (dead) -1 (perfect health) 18. Assumed states of utility scores for bipolar depression /disorder. 18 Decision Tree Analysis From various studies we found the probability of adverse effects that would promote non-compliance, stopping usage, or relapsing back to bipolar depression when initiated with each drug treatment. 5,14,15,19, 20, 17 These were parameters was used in creating a decision tree analysis for SYMBYAX. Parameters: B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 24 Probability score used: • 10 % (0.10) is probability to stop due to adverse events of Lamitrogine in clinical studies.27 • 20% (0.20) is probability to stop due to adverse events of Olanzapine in clinical studies.19 • 10% (0.10) is probability to stop due to of adverse events of Quetiapine in clinical studies.20 • 30% (0.30) is probability to stop due to adverse events of SYMBYAX in clinical studies. 19 B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 25 D E C I S I O N T R E E A N A LY S I S B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 26 R E S U LT S O F D E C I S I O N T R E E A N A LY S I S W I T H R E S P E C T I V E VA L U E S B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 27 C O S T U T I L I T Y A N A LY S I S W I T H R E S P E C T T O QUALITY ADJUSTED LIFE YEARS B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 28 R E S U LT S O F C U A W I T H R E S P E C T T O QUALITY ADJUSTED LIFE YEARS B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 29 Cost Effective Analysis Comparing the drug treatments of Quetiapine, Lamitrogine, Olanzapine and SYMBYAX, SYMBYAX is in favor over the rest because it has the least cost but the most benefits in terms of efficacy of adjusting the quality of life of patients. In other words, SYMBYAX cost more less and has more benefits B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 30 B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 31 B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 32 Expected Value of Costs of Bipolar Depression versus Probability of Adverse Events 5000 4000 3000 Expected value of Costs ($) 2000 1000 0 1 2 3 4 EV Series1 Series2 ADVERSE EVENTS Probability of Adverse Events Decision Analysis for Bipolar Depression In the decision analysis, we observed that SYMBYAX would be the cheapest drug compared to quetiapine, lamitrogine, and olanzapine and it would be more favorable if placed on the formulary. Bipolar disorder/depression drugs are intertwined together such as Olanzapine, Lamitrogine, and Quetiapine which are used to treat bipolar disorder. In our analysis, they observed as dominated drug treatments in expected values costs because they had higher costs but low increase in life years provided for patients if such treatment was implemented into a pharmacy formulary for treatment. Compared to SYMBYAX, they were more expensive in terms of expected value and provide less therapeutic effects or benefits we observed as the increase in life years in patients with bipolar depression. We did also did an incremental ratio of each drug treatment, which showed negative values and the results are informative and supports that SYMBYAX can be effective form of treatment for bipolar depression but this should not be enough to make a final decision for a given budget alone. However concern would be raised against SYMBYAX since it contains olanzapine and the adverse events of SYMBYAX seems similar to olanzapine. There would be concerns about be compliance to the medication in particularly relating to weight gain, somnolence, and diabetes which can affect values of the drug long term on various formulary lists. In conclusion, we chose SYMBYAX based on the incremental cost effectiveness ratio, cost of cost utility analysis, comparing the remission rate would be more cost effective in treating bipolar depression and it should be placed on the formulary as second line treatment instead of first line treatment for bipolar depression. B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 33 Appendix B - REFERENCES 1. Fu A.Z., Krishnan A. A., Harris S.D. Thompson T.R. 2004. The Economic Burden of Bipolar-Related Phases of Depression versus Mania. Drug Benefit Trends; 16(11): 569-575. 2. Simon G. E, Unutzer J. 1999. Health Care Utilization and costs among patients treated for bipolar disorder in an insured population. Psychiatric Services; 50(10) 1303-1308. 3. Parece A, Wu E, Birnbaum H, Greenberg P, et al. Co morbidities and costs associated with bipolar disorder. Poster presentation. 4. Begley C.E. Annegers J.F.; Swann A.C.; Lewis C.; Coan S.; Schnapp W.B.; Bryant-Comstock L. 2001 The Lifetime Cost of Bipolar Disorder in the US: An Estimate for New Cases in 1998. Pharmacoeconomics, 19 (5), pp. 483-495(13) 5. Price N, Davey P, Mudge M, Fitzgerald B et al. 2002 Cost-effectiveness of olazapine versus lithium for the prevention in relapse in bipolar disorder in Australia. Poster presentation. 6. Knoth R L, Chen K, Tafesse E. 2004. Cost Associated with the treatment of patients with Bipolar disorder in a managed care organization. Psychiatric services, 55(12) pg 1353,. http://ps.psychiatryonline.org 7. Gutmnan D, Goodwin GM. Bipolar Depression. Medscape pgs 1-5. http://www.medscape.com/viewarticle/4603047 8. Hirschfield R M, Vornik LA. Bipolar Disorder-Cost and Comorbidity. 2005 The American Journal of Managed Care, 11(3)pg 85-90 9. Martha Sajatovic. 2005 Bipolar Disorder: Disease Burden. American Journal of Managed Care, 11(3)pg 80-84 10. Bowden C.L. 2005. Bipolar Disorder and Work loss. American Journal of Managed Care, 11(3) pg 91-94. 11. Perils R.H. 2005 Managing Bipolar Disorder: Misdiagnosis and quality of life. American Journal of Managed Care, 11(9) pg 267-280. 12. Hirschfield R M, Vornik LA. 2005. Bipolar Disorder: Quality of life and impact of Atypical Antipsychotics. The American Journal of Managed Care, 11(3)pg 85-90 13. Bryant-Comstock L, Stender M, Devercelli G. 2002. Health care utilization and costs among privately insured patients with Bipolar 1 Disorder. Bipolar Disorder Vol. 4; pg 398-405. 14. Yatham LN, LecrubierYF,Davis KH, Harris SD et al. 2004 Quality of life in patients with bipolar disorder I depression: 920 patients. Bipolar disorder Vol 6 pg 379-385. 15. Le Pen C,Levy E, Ravily V, Beuzen JN, Meurgey F. 1994. The cost of treatment dropout in depression. A cost-benefit analysis of Fluoxetine vs.Tricyclics. J .Affect Disorder (1) pg 1-18. 16. Frye M.A, Gitlin M.J., Alttshuler. 2004 Unmet needs of in Bipolar Depression. Depression and Anxiety 19: pg 199-208. B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 34 17. Bridle C, Palmer S, Bagnall A,Darba J, Duffy, Sculpher S, Riemsma R. 2004 A rapid andsystematic reiew and economic evaluation of the clinical and cost effectiveness of newer drugs for treatment of mania associated with bipolar affective disorder. Health Technolgy Assessment; (8) pg 1-226. 18. Aziz M, Merhringer A, Morzurkewich E, Razik G. 2005.Cost-Utility of 2 maintenance treatments for older adults with depression who respond to a course of electroconvulsive therapy: From a decision Analytic Model.Can J Psychiatry; 50 (7), pg 389-397. 19. Tohen M, Vieta E, Calabrese J, Ketter T, et al. 2003 Efficacy of Olanzapine and Olazanpine-fluoxetine Combination in the treatment of Bipolar depression. Arch Gen Psychiatry; 60, pg 1079-1088 20. Calabrese J., Keck P, Macfadden W., Minkwitz M. 2005 A randomized double blinded, Placebo Controlled trial of Quetiapine in treatment of Bipolar I or II Depression. Am J Psychiatry, 162:7 pg 1351-1360. 21. Yatham L, Lecrubier Y, Fieve R, Davis H, et al.2004 Quality of life in patients with bipolar I depression: data from 920 patients. Bipolar disorder; 6 pg 379-385.\ 22. Sajatovic M. Bipolar Disorder. Amer J of Managed Care; 2005, 11(3) pg s80-s84. 23. Namjoshio M, Rajamannar G, Jacobs T, Sanger T et al. 2002 Journal of Affective Disorder;(69) pg 109-118. 24. State of Idaho, Department of Health and Welfare, Division of Medicaid, Pharmacy reimbursement. http://www.healthandwhttp://www.healthandwelfare.idaho.gov/_Rainbow/Documents/m edical/county_drug_file_by%20name.pdf#search='State%20of%20idaho;%20department %20of%20welfare%20and%20health;%20pharmacy%20reimbursement' 25. Schaerer L., Berns S, Born C, Brambillas, et al. Cost effectiveness of olazanpine vs. lithium in bipolar depression. Post presentation at 4th European Stanlry Conference on Bipolar Disorders. 26. Gao K, Calabrease J.2005 Newer treatment studies for bipolar depression. Bipolar Disorder; 7 Suppl. 5:pg13-23. 27. Hurley S. 2002 Lamotrigine Update and its use in mood disorder. The Annals of pharmacotherapy; 36, pg 860-873. 28. Manning S. 2005. Burden of illness in Bipolar Depression. Prim Car companion J Clin Psychiatry; 7(6) 259-267. 29. Revicki D,paramour L, Sommerville K, Swann A, et al. Divalproex sodium versus olanzapine in the treatment of acute mania in bipolar disorder: health-related quality of life and medical cost outcomes. J Clin psychiatry, 2003, 64(3);pg 288-94. 30. Kleinman L, Lowin A, Flood E, Gandhi G, et al. 2003 Pharmacoeconomics; 21(9): pg 601-620. 31. Fankhauser M, (2002). Bipolar Disorder. Dipiro J, Talbert R, Yee G, Matzke G, Wells B, Posey L (ed.), Pharmacotherapy: A Pathophysiologic Approach (p 1265). New York: The McGraw-Hill Companies, Inc. B r o w n , C h a , K i m , a n d L e e T h e r a p e u t i c R e v i e w o f S Y M B YA X f o r B i p o l a r D e p r e s s i o n 35