New Drug Evaluation Monograph Template

New Drug Evaluation Monograph Template Desvenlafaxine (Pristiq™ by Wyeth™)

Executive Summary Desvenlafaxine succinate extended release tablets, (hereafter referred to as desvenlafaxine), is a norepinephrine/serotonin reuptake inhibitor. Desvenlafaxine is a synthetic form of a known active metabolite of venlafaxine. Although kinetic evidence any theoretical supposition support the use of desvenlafaxine as a second line treatment for Major Depressive Disorder (MDD), the published clinical data does not support its use at this time. The published literate studied use of desvenlafaxine for too short a duration of therapy, may or may not have been powered for clinically relevant outcomes (response rate and remission rate), and were never compared to an active control. Side effect patterns were similar to venlafaxine, with nausea being a prevalent (up to 50%) complaint an the chief reason for discontinuation of therapy. External validity of these studies is dubious, as none tested the FDA approved does of 50mg, showed no dose- dependent effects, and failed to control for ethnic backgrounds. Published AWP for Desvenlafaxine makes it an attractive option vs. extended-release venlafaxine. Overall, the lack of both internal and external validity makes it impossible to recommend desvenlafaxine over existing therapy options.

KEY QUESTIONS

1. What is/are the primary/approved indication(s) for Desvenlafaxine? 2. What are the potential secondary/unapproved indications for Desvenlafaxine? 3. How does Desvenlafaxine efficacy compare to the current standard of therapy? 4. How does Desvenlafaxine efficacy compare to comparable therapies? 5. How does Desvenlafaxine safety compare to the current standard of therapy? 6. How does Desvenlafaxine safety compare to comparable therapies? 7. What circumstances would Desvenlafaxine be a recommended therapy? 8. When would Desvenlafaxine not be an appropriate therapy? 9. When would Desvenlafaxine be contraindicated? 10. What are the unanswered clinical questions surrounding Desvenlafaxine?

INDICATIONS

FDA Approved Indication  DSM-IV Major Depressive Disorder (MDD)1

Potential Off Label Uses  Anxiety disorders  Perceived Pain2,3,4 BRIEF BACKGROUND REGARDING CURRENT STANDARD OF THERAPY For Major Depressive Disorder (MDD), there is no single, gold standard treatment modality. Approach to treatment depends on patient preference, compliance, and practitioner assessment.5 For mild to severe depression without psychoses or suicidal ideation, psychotherapy, medications, or both are first line treatments. The specific pharmacotherapy choice depends on patient’s past experience, acceptance, and specific complaints (insomnia, somnolence, pain, etc.).Error: Reference source not found Some common first line pharmacological agents include SSRI, TCAs, DNRTI,SNRI.

Objective assessment of patient’s initial status and progress involved one of several surveys including AMSIT Mental Status Exam, Hamilton Depression Scale (HAM-D17), and a Depression Inventory.6 Adequate response to therapy is defined as a >=50% reduction in Depression scores

Stages of Major Depressive Episode Treatment include Acute (12wks), Continuation (4-9 months) and Maintenance Phases.Error: Reference source not found,Error: Reference source not found

CLINICAL PHARMACOLOGY: Desvenlafaxine is a serotonin/Norepinephrine Reuptake inhibitor (SNRI). It is a synthetic version of an active metabolite of Venlafaxine (Effexor).Error: Reference source not found

PHARMACOKINETICS Parameter Desvenlafaxine Extended Venlafaxine Extend Release Release (Venlafaxine [V] & active metabolite O- desmethylvenlafaxine [ODV]) Route of Admin: Oral extended release tablet Oral extended release tablet Time to Peak: 7.5 hours 5.5hr(V), 9hr(ODV) Bioavailability: 80% 92% (V) Half Life: 11 hours 5 hr(V),11(ODV) Metabolism/Elimination: Renal 45%, UDP-G 19%, CYP2D6 to active ODV and CYP3A4 <5% inactive N- desmethylvenlafaxine, N,O- didesmethylvenlafaxine, Minor Renal clearance(<5%) Effects of Food: Cmax increases 16%, AUC No effect on Bioavailability unchanged Protein Binding Low Low Volume Distribution 3.4L/kg 7.5L/kg (V), 5.7L/kg(ODV) Table 1 Pharmacokinetics of DesvenlafaxineError: Reference source not found compared with Venlafaxine Extended Release7 CLINICAL EFFICACY

Internal Validity In phase III Trials, desvenlafaxine was compared only to placebo. In these trials, primary endpoints were powered to measure a reduction in depression (HAM-D17) scoresError: Reference source not found,Error: Reference source not found,Error: Reference source not found, not the standard response measure of >=50% reduction in depression scoresError: Reference source not found. Response scores were secondary measures, which the studies may or may not have been powered to address. These trials showed erratic reductions in HAM-D17 scores, which did not support a dose-dependent response and somewhat undermined the results.

Response rates varied from 43-60%, which is lower than most current antidepressants, which have a 60-70% response rate.Error: Reference source not found Remission rates of 23-37% for desvenlafaxine are also lower than other antidepressant rates of 30-40%. Of course, generalizations of this nature cannot be made without careful statistical testing, which was beyond the scope of this project.

Treatment duration for the three reviewed trials seemed inadequate, given the staging of MDD. MDD acute phase lasts 12 weeks, while all three reviewed studies only treated patients for 8 weeks.Error: Reference source not found,Error: Reference source not found Typical therapy last not only for the acute phase, but is maintained for an additional 16- 36 weeks during the continuation phase. Error: Reference source not found,Error: Reference source not found Only after the continuation phase is the discontinuation of therapy considered. Although it may not be practical or required to continue therapy for an entire year during a study, it is difficult to determine if desvenlafaxine is an appropriate therapy without these data.

External Validity There may be some differences in efficacy across ethnic backgrounds. One study, with three different dose strengths, showed efficacy in the 100mg and 400mg doses, but no efficacy in the 200mg doseError: Reference source not found. This group had a notably higher proportion of blacks and Hispanics than the other two active groups. The only other study which listed ethnic distributions had a notably higher proportion of blacks and Hispanics in the placebo group vs. the active group. Although kinetic studies have indicated there are no know active metabolites for desvenlafaxine, the possibility of ethnic variations cannot be ruled out.Error: Reference source not found SIDE EFFECTS Side effect profiles were consistent for all three studies evaluated, with nausea being the most profound and prevalent. Although rates varied substantially from study to study, nausea was consistently the most common (30-50% vs placebo 9-11%) complaint and the most common reason for discontinuationError: Reference source not found,Error: Reference source not found,Error: Reference source not found. Suicidal ideation was monitored and was determined to be significant in 1-2 patients in each studyError: Reference source not found,Error: Reference source not found,Error: Reference source not found. Other common side effects were dry mouth, sweating, dizziness, fatigue, constipation, anorexia, and sexual dysfunction.

ALLERGIES AND INTERACTIONS Standard concerns with CNS agents, serotonin agents apply. Taking desvenlafaxine with other serotonin agents is not recommended. Taking MAOI and desvenlafaxine is contraindicated.

There are significant metabolic considerations with desvenlafaxine. Desvenlafaxine is largely renally cleared and should be dose adjusted in cases of renal dysfunction.Error: Reference source not found CYP3A4 inhibitors have a notable effect on desvenlafaxine, with ketoconazole increasing AUC by 43% and Cmax by 8%.Error: Reference source not found No other enzyme interactions were noted.

PRECAUTIONS/CONTRAINDICATIONS Desvenlafaxine, as a SNRI, has rare effects on blood pressure. Patients with hypertension should be monitored for changes due to desvenlafaxine.Error: Reference source not found

Pregnancy Category C – There is no data on the effects of desvenlafaxine in pregnant and lactating womenError: Reference source not found. In rat studies, there were noted effects on pregnancy weight, neonatal deaths, and low neonatal weights.Error: Reference source not found

DOSAGE AND ADMINISTRATION Desvenlafaxine is an extended release formulation approved for 50mg once daily dosing only.Error: Reference source not found Reviewed studies did not show any consistent dose-dependent efficacy, but did show dose-dependent side effects.Error: Reference source not found,Error: Reference source not found,Error: Reference source not found

COST INFORMATION Antidepressant Strength Dose MOA AWP Cost/ Month Desvenlafaxine Extended 50mg Once Daily SNRI $73.57 Release Venlafaxine Extended Release 75mg Once Daily SNRI $110.35 Fluoxetineimmediate release 20mg Once Daily SSRI $79.92 Amitriptyline immediate 75mg Once Daily TCA $21.09 release Table 2 Price Comparisons of Antidepressants for MDD. Adapted from Pharmacist’s Letter.8 CONCLUSIONS AND RECOMMENDATIONS

1. What is/are the Major Depressive Disorder (MDD) primary/approved indication(s) for Desvenlafaxine? 2. What are the  Anxiety disorders potential  Perceived Pain9,10,11 secondary/unapproved indications for Desvenlafaxine? 3. How does There are no published trials comparing Desvenlafaxine desvenlafaxine to other antidepressants. efficacy compare to the current standard of therapy? 4. How does There are no published trials comparing Desvenlafaxine desvenlafaxine efficacy to other antidepressants. efficacy compare to comparable therapies? 5. How does There are no published trials comparing Desvenlafaxine safety desvenlafaxine safety to pharmacological and non- compare to the current pharmacological therapy. standard of therapy? 6. How does There are no published trials comparing Desvenlafaxine safety desvenlafaxine safety to pharmacological and non- compare to pharmacological therapy. comparable therapies? 7. What Desvenlafaxine may be suitable for refractory MDD circumstances would when venlafaxine is not appropriate treatment. Desvenlafaxine be a Patient’s who have failed other antidepressants and recommended who have impaired liver function and are not suitable therapy? candidates for venlafaxine may be candidates for desvenlafaxine. Efficacy in these cases has not been demonstrated, but may be considered when all other pharmacotherapy options have failed and non- pharmacological options are ruled out. 8. When would  Renal impairment Desvenlafaxine not be  Intolerance to venlafaxine formulations an appropriate  Hypertension therapy?  MAOI  When other pharmacological agents have not been tried 9. When would  Renal impairment Desvenlafaxine be  Intolerance to venlafaxine formulations contraindicated?  Hypertension  MAOI 10. What are the  How does desvenlafaxine work for the complete unanswered clinical acute and continuation phases of depression questions surrounding  How does desvenlafaxine compare to other Desvenlafaxine? pharmacological agents  How does desvenlafaxine work in patients with liver dysfunction

DRUG USE CRITERIA Desvenlafaxine has been studied for use in Major Depressive Disorder (MDD) in otherwise healthy patients.Error: Reference source not found,Error: Reference source not found,Error: Reference source not found Desvenlafaxine is FDA approved for MDD only.Error: Reference source not found References 1 Desvenlafaxine package insert. Philadelphia, PA; Wyeth; 2/2008 2 DeMartinis NA, Yeung PP, Entsuah R, Manley AL.A double-blind, placebo-controlled study of the efficacy and safety of desvenlafaxine succinate in the treatment of major depressive disorder. J Clin Psychiatry. 2007;68(5):677-88. 3 Liebowitz MR, Yeung PP, Entsuah R. A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in adult outpatients with major depressive disorder. J Clin Psychiatry. 2007;68(11):1663-72 4 Septien-Velez L, Pitrosky B, Padmanabhan SK, Germain JM, Tourian KA. A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in the treatment of major depressive disorder. Int Clin Psychopharmacol. 2007;22(6):338-47 5 Karasu, TB, Gelenberg, A, Meriam, A, Wang, P. Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Second Edition.. American Psychiatric Association. Retrieved from http://www.psychiatryonline.com/content.aspx?aid=48690 on 04/22/08 6 Applied Therapeutics: The Clinical Use of Drugs 8th ed. Koda-Kimble, MA, Young, LY, Kradjan, WA, Guglielmo, BJ, Alldredge, BK, Corelli, RL. LIppincott Williams & Wilkins 2005 7 Venlafaxine package insert. Philadelphia, PA; Wyeth, 2/2008 8 Comparison of commonly used antidepressants. Pharmacist’s Letter/Prescriber’s Letter 2008;24(5):240509. Retrieved from http://www.pharmacistsletter.com/(S(ok22th45y25x0145y35kdi31))/pl/detaildocuments/240509.pdf? cs=STUDENT&s=PL on 04/24/2008 9 DeMartinis NA, Yeung PP, Entsuah R, Manley AL.A double-blind, placebo-controlled study of the efficacy and safety of desvenlafaxine succinate in the treatment of major depressive disorder. J Clin Psychiatry. 2007;68(5):677-88. 10 Liebowitz MR, Yeung PP, Entsuah R. A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in adult outpatients with major depressive disorder. J Clin Psychiatry. 2007;68(11):1663-72 11 Septien-Velez L, Pitrosky B, Padmanabhan SK, Germain JM, Tourian KA. A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in the treatment of major depressive disorder. Int Clin Psychopharmacol. 2007;22(6):338-47