1. The Role of the Compounding Pharmacist in Hospice and Palliative Care Meeting unique physician and patient needs David J. Miller, R.Ph., Ph.D. Keystone Pharmacy 4021 Cascade Rd SE Grand Rapids, MI 49546 (616) 974-9792 info@keystonerx.com www.keystonerx.com

2. Two Lecture Series Week 1 –Unique challenges in hospice and palliative care –Overview of pharmacokinetics –Different Dosage Forms Available Week 2 –Specific formulations relating to hospice and palliative care patients

3. “There’s nothing else we can do for you”

4. Solve this Puzzle Rules –Connect all 9 dots –Use only 4 lines –Cannot lift pen/pencil –Cannot retrace lines

5. Solve this Puzzle (Solution) Rules –Connect all 9 dots –Use only 4 lines –Cannot lift pen/pencil –Cannot retrace lines

6. Real Life Pain Management Example 67 yo, female, 36kg Terminal cancer, near end of life Severe pain Collapsed Veins NPO Severe Muscle Wasting Rectal fistula Extensive dermal lesions covering entire body, integument compromised

7. Neuropathic Pain Treatment?

13. The Triad Patient Physician Pharmacist The foundation of the profession…the key to compounding

14. Also known as a problem solver, a compounding pharmacist’s ultimate goal in preparing customized medications is to help the physician and patient achieve a more positive therapeutic outcome.

15. Hospice Service Areas

16. Meeting unique needs in:

17. Pain Management Nausea/Vomiting Anxiety Seizures Hyper secretions Xerostomia Wound Care

18. Methods of Medication Administration

19. Oral Nasal Sub-lingual/Buccal Rectal Vaginal Inhalation Transdermal Injectable i.v. i.m. sub-Q intradermal Conjunctival Urethral

20. Pharmacokinetics Absorption Distribution Metabolism Excretion

22. Parenteral Administration Can you name them all?

23. Parenteral Administration Intravenous Intra-arterial Subcutaneous (Sub-Q) Intramuscular Intra-articular Intra-dural Intradermal

24. Order of Speed of Absorption Place in order of speed of absorption –Sub-Q –IV –IM

25. Order of Speed of Absorption IV >> IM > Sub-Q

26. Consider Morphine Peak analgesia occurs with: –20 minutes after IV –30-60 minutes after IM –50-90 minutes after Sub-Q Source: Morphine sulfate for injection package insert: Baxter Corporation

27. Ease of Administration IV <<< IM = Sub-Q

28. Oral Administration Advantages Disadvantages

29. Oral Pharmacokinetics Oral Dosing –Advantage: Easy to administer –Prolonged duration capable –Large surface area of intestinal track usually results in adequate absorption…….but…….

30. Oral Pharmacokinetics Oral Dosing –Disadvantages: Nauseated patients Delayed onset (1-3 hours) Sporadic absorption –Gastric emptying effects absorption –Motility can affect absorption of controlled release or poorly soluble drugs First pass metabolism

31. First Pass Metabolism Primary systems that affect first pass include enzymes of the –Gastrointestinal lumen –Gut wall –Bacteria that colonize the got –Hepatic enzymes

32. First Pass Metabolism

33. Fentanyl Absorption 92% (transdermal) 89% (intranasal) 50% (buccal) 33% (ingestion)

36. Methadone (Dolophine) Increases peak and AUC. Clinically significant effect unlikely, but cannot be ruled out; best to avoid combination. Benzodiazepines, oral: Diazepam (Valium) Midazolam (Versed) Quazepam (Doral) Triazolam (Halcion) Increases AUC and plasma concentrations by inhibiting the intestinal metabolism by CYP3A4. No interaction seen with IV midazolam. Alprazolam does not appear to interact. Watch for possible increased sedation. U.S. prescribing information for midazolam syrup advises avoiding grapefruit. Some references advise avoiding grapefruit with those benzodiazepines listed.

37. Notable Drugs that Experience a Significant Hepatic First-Pass Effect Morphine Midazolam Diazepam Meperidine Lidocaine Buprenorphine Imipramine

38. Tmax for Oral Drug Absorption

39. Pharmacokinetics of Celecoxib

41. Immediate Release Morphine Absorption

43. Buccal/Sublingual Delivery Advantages Disadvantages

44. Buccal Delivery

46. Nasal Delivery Advantages Disadvantages

47. Nasal Delivery of Morphine-Sheep Morphine plasma concentration after nasal administration of morphine formulations in sheep. Mor Sol, morphine solution; Mor Chi Sol, morphine solution containing chitosan; Mor Chi PWD, morphine- chitosan powder; Mor SMS LPC, starch microspheres with lysophosphatidylcholine and morphine as a freeze-dried powder. JPET April 1, 2002 vol. 301 no. 1 391-400

48. Nasal Morphine-Humans Illum LIllum L, Watts P, Fisher AN, Hinchcliffe M, Norbury H, Jabbal-Gill I, Nankervis R, Davis SS. J Pharmacol Exp Ther. 2002 Apr;301(1):391-400.Watts PFisher ANHinchcliffe MNorbury HJabbal-Gill INankervis RDavis SS J Pharmacol Exp Ther. Intranasal delivery of morphine

50. Start here Inhaled opioids achieve rapid but erratic plasma drug levels. Masood and Thomas [5] demonstrated that nebulized morphine achieved peak plasma levels rapidly in all subjects (within 10 minutes) compared with oral morphine but that the variability was greater-from 10 to 30 minutes. Bioavailability was 5.5% (range, 3.2-7.8%) for delivery by inhalation and 24% (15-33%) after oral administration Masood AR, Thomas SH. Systemic absorption of nebulized morphine compared with oral morphine in healthy subjects. Br J Clin Pharmacol. 1996; 41:250-2.

51. Average fentanyl plasma concentration after 100 μg, 200 μg and 300 μg intravenous (i.v., □) and aerosolised pulmonary (a.p., ○) administrations; error bars have been omitted for clarity. From: Br J Clin Pharmacol. 1998 July; 46(1): 37–43.Br J Clin Pharmacol. 1998 July; 46(1): 37–43.

52. Transdermal Advantages Disadvantages

54. The Skin

55. Stratum Corneum

56. Basic Drug Delivery through Skin

57. Hydration Helps

58. Liposomes

59. Stratum Corneum

60. Liposomes

62. Transdermal Fentanyl 2 hour lag time before plasma concentration detected (0.2ng/ml) Levels off between 12 and 24 hours Time to maximum concentration about 30 hours T1/2 after removal 17 hours T1/2 of injectable is 7 hours Depot effect accounts for difference in clearance half-lives

63. Transdermal Fentanyl Tmax Cmax (h) (ng/mL) DURAGESIC® 12 mcg/h 28.8 (13.7) 0.38 (0.13)* DURAGESIC® 25 mcg/h 31.7 (16.5) 0.85 (0.26) DURAGESIC® 50 mcg/h 32.8 (15.6) 1.72 (0.53) DURAGESIC® 75 mcg/h 35.8 (14.1) 2.32 (0.86) DURAGESIC® 100 mcg/h 29.9 (13.3) 3.36 (1.28) *Cmax values dose normalized from 4 x 12.5 mcg/h NOTE: After system removal there is continued systemic absorption from residual fentanyl

64. Rectal Advantage Disadvantage

65. Rectal Dosing Avoids most first pass metabolism Great for nauseated patients Not socially accepted in U.S.

66. Rectal Morphine Sulfate pKa=9

67. Rectal Absorption Variable

68. Inhalation Advantage Disadvantage

69. Inhaled Fentanyl i.v. dose 100mcg Inhaled dose 200mcg

70. Hospice

71. Alternative routes of administration Individualized pain management Nausea & vomiting Inhalation therapy Emergency kits Mouth ulcers Saliva stimulants Adjunctive therapies

72. Hospice MD Anderson Cancer Center Nausea Formula Ativan 1mg Benadryl 25mg Decadron 4mg Haldol 1mg Reglan 10mg Transdermal Gel, Suppositories, Capsules, Troche, Lollipops, Fast Melt Tablets

73. ABH Gel Efficacy 23 patients with chemotherapy induced nausea and vomiting Instructed to apply 0.5ml of an Ativan 1mg/Benadryl 25mg/Haloperidol 1mg/ml gel Not placebo control J Support Oncol.J Support Oncol. 2008 Jan;6(1):27-32. Lorazepam, diphenhydramine, and haloperidol transdermal gel for rescue from chemotherapy-induced nausea/vomiting: results of two pilot trials. Bleicher J, Bhaskara A, Huyck T, Constantino S, Bardia A, Loprinzi CL, Silberstein PT.Bleicher JBhaskara AHuyck TConstantino SBardia ALoprinzi CL Silberstein PT

74. ABH Gel Efficacy Phase 1 –17/23 (74%) reported that the application of the gel decreased their CINV –15/23 (70%) reported relief within 30 minutes of application –3 patients believed gel caused sedation J Support Oncol.J Support Oncol. 2008 Jan;6(1):27-32. Lorazepam, diphenhydramine, and haloperidol transdermal gel for rescue from chemotherapy-induced nausea/vomiting: results of two pilot trials. Bleicher J, Bhaskara A, Huyck T, Constantino S, Bardia A, Loprinzi CL, Silberstein PT.Bleicher JBhaskara AHuyck TConstantino SBardia ALoprinzi CL Silberstein PT

75. ABH Gel Efficacy Phase 2 –All 10 patients believed treatment was effective –CINV decreased from 6.1/10 before application to 1.7/10 30 minutes following application But……. J Support Oncol.J Support Oncol. 2008 Jan;6(1):27-32. Lorazepam, diphenhydramine, and haloperidol transdermal gel for rescue from chemotherapy-induced nausea/vomiting: results of two pilot trials. Bleicher J, Bhaskara A, Huyck T, Constantino S, Bardia A, Loprinzi CL, Silberstein PT.Bleicher JBhaskara AHuyck TConstantino SBardia ALoprinzi CL Silberstein PT

76. ABH Gel Efficacy Phase 2 –All 10 patients believed treatment was effective –CINV decreased from 6.1/10 before application to 1.7/10 30 minutes following application But……. J Support Oncol.J Support Oncol. 2008 Jan;6(1):27-32. Lorazepam, diphenhydramine, and haloperidol transdermal gel for rescue from chemotherapy-induced nausea/vomiting: results of two pilot trials. Bleicher J, Bhaskara A, Huyck T, Constantino S, Bardia A, Loprinzi CL, Silberstein PT.Bleicher JBhaskara AHuyck TConstantino SBardia ALoprinzi CL Silberstein PT

77. ABH Gel Efficacy A/B/H Gel Application does NOT produce systemic drug concentrations –10 healthy volunteers age 25-58 received 1ml of A/B/H 2/25/2mg/ml gel in PLO rubbed on volar wrist –Blood samples collected at 0, 30, 60,90,120, 180 and 240 minutes Pain Symptom Manage.Pain Symptom Manage. 2012 May;43(5):961-6. doi: 10.1016/j.jpainsymman.2011.05.017. ABH gel is not absorbed from the skin of normal volunteers. Smith TJSmith TJ, Ritter JK, Poklis JL, Fletcher D, Coyne PJ, Dodson P, Parker G.Ritter JKPoklis JLFletcher DCoyne PJDodson PParker G

78. ABH Gel Efficacy No lorazepam or haloperidol detected in any of the 10 volunteers down to a level of 0.05ng/ml Diphenhydramine was detectable in 5/10 patients at 240 minutes Not believed to be absorbed in sufficient quantities to relieve nausea/vomiting Pain Symptom Manage.Pain Symptom Manage. 2012 May;43(5):961-6. doi: 10.1016/j.jpainsymman.2011.05.017. ABH gel is not absorbed from the skin of normal volunteers. Smith TJSmith TJ, Ritter JK, Poklis JL, Fletcher D, Coyne PJ, Dodson P, Parker G.Ritter JKPoklis JLFletcher DCoyne PJDodson PParker G

79. Conscious Sedation Study in Children Receiving Chemo Ljungman, et. Al (2000). Midazolam Nasal Spray Reduces Procedural Anxiety in Children. Pediatrics 105:73-8

80. Tolerability of ABHR in Hospice Patients Retrospective cohort study 11,181 ABHR Rxs dispensed to 8600 hospice patients Well tolerated with only 0.1% experiencing extraparamidal symptoms (42 patients total) J Palliat Med.J Palliat Med. 2005 Dec;8(6):1135-43. Tolerability of the compound ABHR in hospice patients. Weschules DJWeschules DJ.

81. Initial Selection of Antiemetics in End-of-Life Care: A Retrospective Analysis Author(s): Tolen Laura, McMath Jill A, Alt Calvin, Weschules Douglas J, Knowlton Calvin H, McPherson Mary Lynn Int J Comp Pharm Mar/Apr 2006

85. Wound Management Treatment Approach Either Singularly Focused or Multifaceted –Healing agents –Granulating agents –Allergy modulators –Pain control –Control of underlying inflammation –Infection Control

86. Misoprostol MOA: –Synthetic prostaglandin E1 analogue –Mucosal cytoprotectant –Promote cell growth, mucous secretion, promotes cellular migration to area, vasodilation Indicated for the prevention of NSAID-induced gastric ulcers Adverse effects: –Abdominal pain, diarrhea –Black Box Warning: can cause abortion, premature birth, or birth defects during pregnancy Misoprostol. Micromedex.2012 [cited 2012 Sept 28]. Available from: http://0- www.thomsonhc.com.libcat.ferris.edu/micromedex2/librarian/PFDefaultActionId/evidencexpert.DoIntegratedSearch

87. Phenytoin MOA: –Promotes wound healing by stimulating fibroblast proliferation, inhibiting collagenase enzymes, and antibacterial activity. –Contributes to topical pain relief Adverse Effects: –Rash, constipation, coordination problems Phenytoin. Micromedex. 2012 [cited 2012 Sept 28]. Available from: http://0- www.thomsonhc.com.libcat.ferris.edu/micromedex2/librarian/PFDefaultActionId/evidencexpert.DoIntegratedSearch

88. Baharvand M. et al. Efficacy of topical phenytoin on chemotherapy- induced oral mucositis Outcomes: –Daily pain severity was reported: 0 (no pain) to 10 (worst pain) –Quality of life questionnaire Phenytoin 0.5% oral rinse vs. placebo solution –Given 4 times per day until lesions were healed or a maximum of 2 weeks Baharvand M, Sarrafi M, Alavi K, Moghaddam EJ. Efficacy of topical phenytoin on chemotherapy-induced oral mucositis; a pilot study. DARU Jor of Pharm Sci. 2010 [cited 2012 Sept 25] 18(1)46-50. Available from: http://0-www.ncbi.nlm.nih.gov.libcat.ferris.edu/pmc/articles/PMC3232086/

89. Baharvand M. et al. Results –No lesions appeared after 2 weeks in the phenytoin group –Duration of lesions lasting (p=0.008): Phenytoin= 4.5 days(median) Control= 6 days (least amount of time) –Pain: Pain score dropped gradually, but no significant difference between phenytoin and control –Quality of life: Base LineWeek 1Week 2 PhenytoinControlPhenytoinControlPhenytoinControl Mean Value70.271.851.766.845.553.7 P-value 0.851 0.0220.093 Baharvand M, Sarrafi M, Alavi K, Moghaddam EJ. Efficacy of topical phenytoin on chemotherapy-induced oral mucositis; a pilot study. DARU Jor of Pharm Sci. 2010 [cited 2012 Sept 25] 18(1)46-50. Available from: http://0-www.ncbi.nlm.nih.gov.libcat.ferris.edu/pmc/articles/PMC3232086/

90. Lidocaine MOA: –Blocks initiation and conduction of nerve impulses  local anesthesia –Produces an analgesic effect Adverse Effects: –Drowsiness, dizziness, hypotension, cardiac dysrhythmia Lidocaine. Micromedex. 2012 [cited 2012 Sept 29]. Available from: http://0- www.thomsonhc.com.libcat.ferris.edu/micromedex2/librarian/PFDefaultActionId/evidencexpert.DoIntegratedSearch

91. Diphenhydramine MOA: –Acts as an antihistamine by competing with histamine at receptor sites Adverse effects: –Xerostomia, somnolence, dizziness

92. Tranilast MOA: –inhibits the release of histamine from mast cells –was previously reported to suppress collagen synthesis of fibroblasts derived from keloid tissues Suzawa H, Kikuchi S, Arai N, Koda A. Japanese Journal of Pharmacology [1992, 60(2):91-96]

93. Dosage Forms

94. Compounded Dosage Forms Oral capsules and liquids Transdermals Lollipops and popsicles Rapid Dissolve Tablets (RDT, Quick-Melt ® ) Troches, tablet triturates and sublingual drops Suppositories, enemas and rectal rockets Nasal and otic preparations Topical creams, ointments, gels, powders and sprays Oral adhesives, mouthwashes and rinses Sterile products –inhalation solutions, injections, ophthalmics, TPNs

95. Compounded Capsules Medications formulated in capsules enable the patient to get the exact dosage needed, while avoiding unwanted dyes and fillers.

96. Sustained Release Capsules Methocel E4M

97. Compounded Oral Liquids Preparing medications in a liquid form allows the patient who can’t swallow pills to get the appropriate medicine in a vast range of flavors, such as tutti-frutti or vanilla butternut.

98. Compounded Oral Liquids Difficulty swallowing –Medication not available as liquid –Infants, children, geriatrics, hospice Avoid unwanted ingredients –Free of alcohols, dyes, preservatives and sugars Increased compliance –Much more palatable preparations with choice of multiple sweeteners and flavors Anhydrous formulations –May be used if aqueous stability a concern

99. Transdermal Gels A specially prepared emulsion that penetrates the skin and gets medications into the bloodstream quickly Effective dosage form for the patient who can’t swallow May be used for systemic or local effects

100. Transdermal Drug Delivery Drug Classes Used in Transdermals Analgesics Narcotics Non-narcotics Atypical analgesics –Sympatholytic agent –NMDA-Calcium channel blocker –AMPA-Sodium channel blocker –Alpha agonist –Gaba agonist –Mu agonist –Substance P blocker

101. Transdermal Drug Delivery Drug Classes Used in Transdermals NSAIDs Muscle relaxants Anti-nausea agents Antiviral agents Anti-inflammatory agents Anesthetics Anti-anxiety agents

102. Medicated Lollipops Local effects –Anesthetic –Anitemetic –Antifungal –Antiviral –Anti-inflammatory –Saliva stimulant –Healing agents

103. Medicated Lollipops Systemic effects –Anti-anxiety –Appetite Suppressants –Antipyretic –Analgesic Narcotic Non-narcotic

104. Medicated Lollipops Combination effects –Smoking deterrent –Cold preparations Cough suppressant Decongestant Antihistamine Sore throat –Antibiotic –Antihistamine

105. Troches Soft gelatin-flavored troches, like gummy bears or chewable troches, provide medication in an easy-to-take and pleasant tasting form.

106. Troches Local effects for better therapeutic outcome –Antiviral or antifungal -Anti-inflammatory –Anesthetic -Healing agents –Saliva stimulant Sublingual / buccal absorption –Convenience –Faster onset of action –No “first-pass” effect –No stomach acid degradation

107. Troches Systemic effects for better therapeutic outcome –Antiemetic –Pain Management –Anxiolytic

108. Tablet Triturates and Rapid Dissolving Tablets (RDT’s) Rapid onset –Migraine headache –Emesis (canine use) –Erectile dysfunction Sublingual absorption –No first-pass effect –No stomach acid degradation Cost effective Convenient

109. Compounded Sterile Products Injections -- aqueous and oil vehicles Ophthalmics -- solutions, suspensions, sprays, and ointments TPNs and IV admixtures Inhalation solutions –Combine multiple ingredients to improve compliance Irrigating solutions

110. Suppositories Putting medicine into suppositories allows the patient who can’t swallow to receive the required drug.

111. Suppositories and Enemas Rectal or vaginal use Difficulty in swallowing Nausea/vomiting Injections cause pain, anxiety Rapid local affect –Hemorrhoids –Irritable Bowel Syndrome (Crohn’s disease) –Anesthetic, anti-inflammatory, steroid agents Good absorption route for many drugs –Prevents 2/3 of first-pass effect

112. The Rectal Rocket Designed to get the drug(s) to the sight of action Holds drug(s) at sight of action for an extended period of time (air vent included) Combine anesthetic and anti-inflammatory drugs, or use for healing

113. Topical Sticks and Tubes Dispensing medication in deodorant stick or chapstick-like containers allows the patient to self-administer drugs easily for PRN doses. Tubes allow creams, ointments and gels to be relatively light and oxidation-free.

114. Medicated Powders Try a combination of an antifungal, antibiotic, antiviral, steroid and an anesthetic with an oral adhesive for canker sores or other oral lesions.

115. Compounded Topical Formulations Creams –Water-in-oil emulsions –Oil-in-water emulsions Ointments –Anhydrous vehicles: PEG, Petrolatum Gels –Carbomer, HEC, HPC, HPMC Sprays Specialty deodorant stick or lipstick forms Penetration agents to enhance effects

116. The Polyox Bandage Designed for oral use Superior oral bandage –Stays in place for hours even if “rubbed” Used for any drug therapy desired –Antihistamine, anesthetic, antiviral, antifungal, anti- inflammatory, etc., or combinations Also used for wound care –No touching of wound for application –No removal of new tissue growth –Advantageous in oozing wound

117. Nasal and Otic Preparations Nasal –Rapid absorption of drug –Pump metered spray bottle delivers accurate dose of drug –Studies show good absorption route Otic –Anhydrous vehicles PEG, Sweet Oil, Propylene Glycol, Glycerin –Combine multiple medications Anesthetic, anti-inflammatory, antibiotic, antifungal, antiviral, steroid, etc. Gels –Carbomer, HEC, HPC, HPMC

118. Compounded Inhalation Solutions Combination therapies for improved compliance –Hospice use (Inhaled Morphine) –ID (Inhaled Antimicrobials) Formulations not commercially available Veterinary applications

119. Medication Baby Bottle The medication baby bottle is an effective device to get accurate doses into an infant.

120. Questions?