PRESCRIPTION WEIGHT-LOSS MEDICATION. Najla Lakkis, MD, MPH Oct 6, 2012

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1 PRESCRIPTION WEIGHT-LOSS MEDICATION Najla Lakkis, MD, MPH Oct 6, 2012

2 Epidemy of Obesity Lebanon: the prevalence of overweight and obesity in the adults aged 20 years reached 37.0% and 11.0% respectively in 2009 compared to 37.0% and 7.3% in U.S. population: 1/3 of adults are overweight and another 1/3 are already obese. Nasreddine L. et al. BMC Public Health 2012, 12:798

3 Epidemy of Obesity in Lebanon by Age/Gender Nasreddine L. et al. BMC Public Health 2012, 12:798

4 Excessive Body Weight Physical & Psychologic Complications Hypertension Dyslipidemia Type 2 diabetes mellitus Heart disease Stroke Certain types of cancer (endometrial, breast, prostate, colon) Gallbladder disease Sleep apnea and other respiratory problems Reduced fertility Osteoarthritis Increase in all-cause mortality Emotional distress Discrimination Social stigmatization

5 PRESCRIPTION WEIGHT LOSS MEDICATIONS They are indicated, as per the FDA, as an adjunct to a reduced-calorie diet & exercise for chronic weight management with initial BMI 27 kg/m 2 with at least 1 weight-related comorbid condition (eg, HTN, DM, dyslipidemia).

6 REMEMBER -SERIES OF FDA REJECTIONS Weight loss drugs in general have not had a great track record for safety.. Fenfluramine+Phentermine combination and Dexfenfluramine were withdrawn from the market in 1997 due to heart valve damage Rimonabant was formally rejected by the FDA in 2007(risk of serious psychiatric problems and even suicide). Sibutramine was also pulled from pharmacy shelves in 2010 due to concerns about heart problems ( cardiovx events & strokes). The FDA also formally rejected: Lorcaserin from Arena Pharmaceuticals in October Phentermine + Topiramate ER (Qnexa) from Vivus in October Bupropion+ Naltrexone (Contrave) from Orexigen Therapeutics in Feb The FDA asked the maker of Contrave, to check for heart attack or other cardiovascular risks by conducting a randomized, double-blind, placebo-controlled trial..

7 LORCASERIN HYDROCHLORIDE marketed as Belviq (BEL-VEEK) in the US made by Arena Pharmaceuticals Rejected by the FDA in October 2010 (because of concerns of an increased CARDIOVX risk of heart disease and stroke among users) Approved by the FDA in June 2012

8 LORCASERIN: Mechanism of Action It is a SELECTIVE serotonin 2C (5-HT2C) receptor agonist It activates brain receptors for serotonin, a neurotransmitter that triggers feelings of satiety and satisfaction. At dosages intended for weight loss, it does not significantly turn on different serotonin switches responsible for the effects of hallucinogens (such as LSD) and addictive drugs of abuse. Higher doses may trigger these switches. Fryhofer S. Sep Astrup A. & Pedersen S. Jun

9 LORCASERIN: Dosage Forms & Strengths Belviq 10-mg tablets Once to BID ± food. It will become available in the US by early It has a potential for abuse... It will be a controlled substance

10 LORCASERIN: Dose Adjustment Renal impairment Mild (CrCl ml/min): No dosage adjustment required Moderate (CrCl ml/min): Use caution Severe (CrCl <15 ml/min) or ESRD: Not recommended Hepatic impairment Mild-to-moderate (Child-Pugh score 5-9): No dosage adjustment required Severe (Child-Pugh score >9): Use caution

11 CHILD-PUGH SCORE The score employs five clinical measures of liver disease. Each measure is scored 1-3, with 3 indicating most severe derangement.

12 LORCASERIN: How Well Does It Work? One should expect at least 5% body weight loss overall. If this result isn't evident after taking it for 3 months, the patient should stop the drug. Clinical trials have shown that Lorcaserin produces about 4 kg of weight loss over a 1-year period compared with placebo, with some sustained weight loss benefit after 2 years of treatment. Thus, the weight loss seen with Lorcaserin is slightly greater than that seen with Orlistat, which provides 2-3 kg of placebo-subtracted weight loss. Fryhofer S. Sep Astrup A. & Pedersen S. Jun Fidler MC, et al. J Clin Endocrinol Metab. 2011;96:

13 LORCASERIN in persons with Type 2 DM It improves glycemic control (A1c by 1%) in addition to facilitating weight loss (5%). It has modestly beneficial effects on Lipids & BP. Symptomatic hypoglycemia occurred in 7.4% of patients on Lorcaserin twice daily, 10.5% on Lorcaserin once daily, and 6.3% on Placebo. In this clinical trial, all patients were concomitantly using a sulfonylurea (±metformin). Lorcaserin has not been studied in patients taking Insulin. Astrup A. & Pedersen S. Jun O'Neil PM, et al. Obesity doi: /oby

14 LORCASERIN: Limitations of Use -1- The safety and efficacy of coadministration of Lorcaserin with other products intended for weight loss including prescription drugs (e.g., Phentermine), OTDs, and herbal preparations have not been established. The effect of Lorcaserin on cardiovx morbidity&mortality has not been established. N.B. Preliminary data suggest that 5HT2B receptors may be overexpressed in CHF The FDA is requiring 6 postmarketing studies, including a long-term cardiovx trial to evaluate risk for heart attack and stroke. Astrup A. & Pedersen S. Jun

15 LORCASERIN: Limitations of Use -2- Risk of Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions if combined with: 1. Serotonergic medications, including: SSRIs & SNRIs 2. Drugs that may affect the serotonergic neurotransmitter systems Triptans, MAOIs TCAs Lithium Bupropion Tramadol Tryptophan St. John's Wort Antipsychotics or other dopamine antagonists.

16 LORCASERIN: Limitations of Use -3- Lorcaserin should be used with caution in men who have conditions that might predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia), or in men with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie's disease). There is limited experience with the combination of Lorcaserin & medication for erectile dysfunction (e.g., phosphodiesterase 5 inhibitors). Therefore, the combination with these medications should be used with caution.

17 LORCASERIN: Contra-Indications Pregnancy &?Breastfeeding Children < 18year old (not studied yet) Patient with Severe Renal Failure. Patients on Serotonergic Medications. Patients with CHF or hemodynamically-significant VHD. Patient who have conditions that might predispose them to priapism.

18 Lorcaserin: Adverse Effects-common >10% % C % P Headache URTI Nasopharyngitis % % % Dizziness Nausea Fatigue Diarrhea UTI Back pain Constipation Dry mouth Vomiting Rash Musculoskeletal pain

19 Lorcaserin: Adverse Effects-others Cognitive Impairment such memory problems and attention disturbance (1.9% c versus 0.5% p ) Psychiatric Problems such as euphoria, hallucination, and dissociation (0.2% c versus <0.1% p ) Discontinue Loraceserin in patients who experience suicidal thoughts or behaviors Hematological Changes: WBC count, lymphopenia & neutropenia (0.4% c vs 0.2% p ) RBC count, Hb, HTC (1.3% c vs 1/.2% p ) Prolactin Elevation

20 ATTENTION Monitor for serotonin syndrome or NMS-like reactions Studies suggest possibility of regurgitant VHD (not likely), monitor if patient has CHF Advise patient to take caution when operating hazardous machinery. Monitor for worsening of depression, suicidal thoughts or behavior, or any other unusual changes in mood or behavior Monitor for hypoglycemia with type 2 DM, if hypoglycemia occurs while on therapy, adjust antidiabetic drug regimen Caution in men with predisposed conditions to priapism (eg sickle cell anemia, multiple myeloma, or leukemia) or anatomical deformation of the penis Caution with bradycardia or a history of heart block May cause decrease in WBC count and other hematological changes, consider periodic monitoring of CBC Moderately elevates prolactin levels May cause pulmonary hypertension (insufficient data)

21 PHENTERMINE HYDROCHLORIDE + TOPIRAMATE EXTENDED-RELEASE marketed as Qsymia (kyoo-sim-ee-uh) made by Vivus Pharmaceuticals Rejected by the FDA in Oct 2010 (Qnexa) because it increased cardiovx risk Approval by the FDA in Jul 2012 (Qsymia)

22 Phentermine+Topiramate ER It is a combination of 2 currently approved drugs: The sympathomimetic amine anorectic Phentermine, the safer "phen" part of the infamously unsafe fen-phen diet drug combo. It triggers release of Norepinephrine Leptin in blood appetite The seizure/migraine drug Topiramate, that causes weight loss in several ways: increasing feelings of fullness making foods taste less appealing increasing calorie burning.

23 PHEN/TPM ER: Dosage Forms & Strengths Qsymia 3.75 mg/23mg (14 and 30 capsules), Qsymia 7.5 mg/46 mg (30 capsules), Qsymia mg/69 mg (30 capsules), Qsymia 15 mg/92 mg (30 capsules). Start with 3.75 mg/23mg, and to the recommended dose 7.5 mg/46 mg after 14 days. Evaluate weight loss after 12 weeks before shifting to a higher dose then 12 weeks The combination is taken once a day in the morning ± food. Qsymia should become available by Sep It will be sold only through "certified pharmacies because women taking this medication must use birth control, and the drug Phentermine has a known potential for abuse.

24 PHEN/TPM ER: Dose Adjustment Renal impairment: Mild ( 50 ml/min): No dose adjustment required Moderate (30-49 ml/min) and severe (<30 ml/min): Not to exceed 7.5 mg/46 mg qday Hepatic impairment: Mild (Child-Pugh 5-6): No dose adjustment required Moderate (Child-Pugh 7-9): Not to exceed 7.5 mg/46 mg qday Severe (Child-Pugh 10-15): Avoid use

25 PHEN/TPM ER: How Well Does It Work? 2 year-long clinical trials (n 3700 patients) reported 6.7%-8.9% additional weight loss in patients taking Qsymia compared with those taking the placebo. After 3 months of treatment, one can expect at least: 3% weight loss on lower doses 5% weight loss on higher doses. If not, the drug should be stopped, but gradually: Discontinue Qsymia 15mg/92mg gradually by taking a dose every other day for at least 1 week prior to stopping treatment altogether, due to the possibility of precipitating a seizure. Gadde KM et.al. Lancet Apr 16;377(9774):

26 56-week Randomized Clinical Trial (EQUIP Trial) in Severely Obese Patients BMI % 5.1% 10.9% p < Allisson D et.al. Obesity (Silver Spring) February; 20(2):

27 56-week Randomized Clinical Trial (EQUIP Trial) in Severely Obese Patients BMI 35 The 15/92 group had significantly greater changes relative to placebo for WC, SBP & DBP, FBS, TGs, T. Cholesterol, LDL-C, & HDL-C. Allisson D et.al. Obesity (Silver Spring) February; 20(2):

28 PHEN/TPM ER: Limitations of Use The safety and effectiveness of Qsymia in combination with other products intended for weight loss, including prescription and OTC drugs and herbal preparations have not been established. The effect of Qsymia on cardiovx morbidity&mortality has not been established. The FDA is requiring Qsymia manufacturer Vivus, Inc. to conduct 10 postmarketing studies, including 1 long-term study specifically looking at cardiovx events, including heart attack and stroke. Lauer MS. Lemons for obesity. Ann Intern Med. 2012,157: Adamson Fryhofer S.-

29 PHEN/TPM ER: Common Side Effects 4 Clinical Trials Experience CNS: paresthesia*, headache*, dizziness*, dysgeusia, hypoesthesia, disturbance in attention Psychiatric: insomnia*, depression*, anxiety* GI: constipation*, dry mouth*, nausea, diarrhea, dyspepsia, heartburn General: fatigue, irritability* Eye Disorders: blurred vision* Infections: URTI, nasopharyngitis, sinusitis, bronchitis, UTI, gastroenteritis Laboratory Abnormalities: CO2 content; K + ; Creat Weight loss may the risk of hypoglycemia in patients with type 2 DM treated with insulin and/or insulin secretagogues. Weight loss may the risk of hypotension in patients on anti-hypertensive drugs.

30 Common Side Effects Post-Marketing Phentermine Allergic: Urticaria Cardiovx : BP, Ischemic events CNS: Euphoria, Psychosis, Tremor Reproductive: Changes in libido, Impotence Topiramate Dermatologic: Bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), Pemphigus Gastrointestinal: Pancreatitis Hepatic: Hepatic failure (including fatalities), Hepatitis Metabolic: Hyperammonemia Hypothermia Ophthalmic: Maculopathy

31 DRUG-DRUG INTERACTION MAOIs. Carbonic Anhydrase Inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide). OCPs: increased exposure to the progestin and lower exposure to the estrogen irregular bleeding (spotting) CNS Depressants (barbiturates, benzodiazepines, sleep medications) including Alcohol: may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Non- K + Sparing Diuretics: K + (Monitor K + level). Antiepileptic Drugs: Carbamazepine or Phenytoin plasma concentrations of topiramate by 40-48% Valproic A. hyperammonemia ± encephalopathy. hypothermia ± hyperammonemia

32 Warnings & Precautions Fetal Toxicity (Topiramate in T1: Cleft Lips ± Palate). in HR, so HR monitoring is recommended. Suicidal Behavior and Ideation (Topiramate) Acute Myopia and Secondary Angle Closure Glaucoma Mood and Sleep Disorders (++Avoid Alcohol intake) Cognitive Impairment e.g., impairment of concentration, difficulty with memory, and speech or language problems, particularly word-finding difficulties). Metabolic Acidosis

33 Contre-Indications Hypersensitivity to sympathomimetic amines Pregnancy or Planning for Pregnancy or no effective Contraception method Unstable heart disease or stroke Glaucoma Hyperthyroidism Severe Liver Failure Use of Phentermine is contraindicated during or within 14 days following MAOIs -- risk for hypertensive crisis Use of Topiramate is contraindicated during Carbonic Anhydrase Inhibitor due to risk of metabolic acidosis and risk of kidney stone formation.

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35 ORLISTAT Modest weight loss an average of 2.9 kg at 1 to 4 years Little information on its effect on longer-term complications of obesity Rucker D et al. BMJ 2007, 335 (7631): Wood S. Medscape News. Retrieved 26 April 2011.

36 ORLISTAT: Story with the FDA 1999: The FDA approved Orlistat capsules as a prescription drug to treat obesity. 2007: The FDA approved Orlistat capsules (60mg) as an OTC weight loss aid for overweight adults. Orlistat capsules (120mg) remained a prescription drug for obesity in the USA. 2010: new FDA safety information about cases of severe liver injury with hepatocellular necrosis or acute hepatic failure that have been reported rarely (n=13) with the use of this medication (60mg and 120mg). Some of these cases resulting in liver transplant (n=3) or death (n=2).

37 ORLISTAT: Mechanism of Action It inhibits gastric and pancreatic lipases TGs from the diet are not hydrolyzed into absorbable free fatty acids, and are excreted undigested instead. Only trace amounts are absorbed systemically. It prevents approximately about 25% (60mg TID) to 30% (120mg TID) of dietary fat from being. Higher doses do not produce more potent effects.

38 ORLISTAT: Dosage Forms & Stengths Orlistat 60mg (Alli -GSK) TID Orlistat 120mg (Xenical -Roche) TID with each main meal containing fat (during or up to 1 hour after the meal)

39 ORLISTAT: How Well Does It Work? The weight loss achieved with Orlistat varies. In 1- year clinical trials: 35.5%-54.8% achieved 5% or greater decrease in BMI 16.4%- 24.8% achieved at least a 10% decrease in BMI After Orlistat was stopped, a significant no. of subjects regained up to 35% of the weight they had lost. The incidence of T2DM in an obese population over 4 yrs is decreased with Orlistat (6.2%) compared to placebo (9.0%). * Long-term use of Orlistat also leads to a modest reduction in BP. ** *Torgerson J et al. Diabetes Care 2004, 27 (1): **Siebenhofer A et al. Cochrane Database Syst Rev 2009, 8 (3): CD

40 ORLISTAT: Common Side Effects Clinical Trials Experience High rates of GI side effects: oily stool / spotting, passing gas with oily discharge, stool incontinence, diarrhea, nausea/vomiting absorption of fat soluble vitamins (D, E, K) & betacarotene better to take supplements once a day at least 2 hrs before or after the administration of Orlistat, such as at bedtime. Rare cases of hypersensitivity: pruritus, rash, urticaria, angioedema, bronchospasm and anaphylaxis. Very rare cases of bullous eruption.

41 ORLISTAT: Side Effects Postmarketing Surveillance risk for severe liver injury. in transaminases & alk. Phosphatase. risk for gall stones. risk for the development of kidney stones (oxalate-induced acute kidney injury). risk for acute kidney injuries. risk for acute Pancreatitis. Wood S. Medscape News. Retrieved 26 April

42 ORLISTAT: Drug-Drug Interactions It can impair absorption of: Vit K: INR in patients on Orlistat & Warfarin. Levothyroxine: administer it at least 4 hrs before Orlistat. Cyclosporine: administer it 3 hrs after Orlistat. Amiodarone.

43 ORLISTAT: Contre-indications Pregnancy. It is not known if Orlistat passes into breast milk. Hypersensitivity to Orlistat or to any of its components Chronic Malabsorption Syndrome. Gallbladder problem (cholestasis) or Reduced gallbladder function (e.g. after cholecystectomy). Impaired Liver Function. Pancreatic Disease. Kidney stones/problems (such as calcium oxalate kidney stones, hyperoxaluria). Organ Transplant. Anorexia Nervosa/Bulimia.

44 BUPROPION+ NALTREXONE marketed as Contrave made by Orexigen Therapeutics

45 BUPROPION+ NALTREXONE Both drugs have been on the market for about 25 yrs. Bupropion, commonly prescribed to treat depression and also approved to help people quit smoking, curbs the appetite. Naltrexone, an opioid blocker, approved to treat opioid and alcohol addictions, amplifies the effect of Bupropion on the appetite. Most patients taking this combination in clinical trials lost about % of their starting body weight compared to those taking a placebo, which is below the FDA standard of 5%.

46 BUPROPION+ NALTREXONE Dec 7, 2012 An FDA advisory committee voted 13 to 7 to recommend approval of Contrave. But many of the FDA committee members expressed concern about: 1. the drug's impact on cardiovascular health ( BP) 2. The lack of data that give any clues about the drug's safety or efficacy beyond the one-year mark for a long-term health condition.

47 BUPROPION+ NALTREXONE Feb. 1, 2011 The FDA has decided not to approve the weight loss drug Contrave. The FDA issued a response letter that asks Orexigen Therapeutics, the maker of Contrave, to check for heart attack or other cardiovascular risks by conducting a randomized, double-blind, placebocontrolled trial.