藥用⼤麻中之⼤麻⼆酚 Cannabidiol in Medical Marijuana

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藥用⼤麻中之⼤麻⼆酚

Cannabidiol in Medical Marijuana

李秀芬

台中榮總兒童醫學中⼼兒童神經科

卓⾶病友會 2020.10.24 西湖渡假村

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學習⼤綱

• ⼤麻 (Cannabis)簡介

• ⼤麻⼆酚 (CBD; cannabidiol ) 治療⼈類疾病的作用機轉

• ⼤麻⼆酚 (CBD; cannabidiol ) 治療癲癇的可能作用機轉

• ⼤麻⼆酚 (CBD; cannabidiol ) 的製造、合成、代謝及藥物動⼒學特點

• 市售藥用⼤麻⼆酚 (CBD; cannabidiol )

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⼤麻 (Cannabis)簡介 Introduction of cannabis

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⼤麻相關名詞 (Terms related to cannabis)

Terms

• ⼤麻 (Cannabis) • 開花植物屬，包含熟知的熱帶⼤麻及印度⼤麻，西元前2700年已被中國神農⽒用於醫療(A genus of flowering plant with several recognized species such as sativa and indica. This plant is widely distributed and perhaps one of the oldest plants cultivated for human use. Its use had been described in Chinese pharmacopeias even around BCE 2700 for a number of medicinal indications by Emperor Shen Nung)

• ⼤麻 (Marijuana) • 乾燥的⼤麻葉及花 (A dried mixture of cannabis leaves and flowers)

• 藥用⼤麻

(Medical marijuana) • 醫療用的⼤麻或⼤麻製品 (Use of cannabis or cannabis product for medical purpose)

• 麻 (Hemp) • 熱帶⼤麻莖幹中豐富的纖維，含微量四氫⼤麻酚及少量⼤麻⼆酚 (The hearty fibers in the stalk and stems of the plant Cannabis sativa L. It contains minimal amounts of THC and low levels of CBD)

• 麻油 (Hemp oil) • 麻植物種⼦取得，內含可忽略的⼤麻素 (Obtained from the seeds of the hemp plant and contains a negligible amount of cannabinoids)

• ⼤麻⼆酚油 (CBD oil) • 麻植物的花取得，不含四氫⼤麻酚 (Obtained from the flowering portion of the hemp plant and does not contain THC)

• ⼤麻油 (Cannabis oil ) • 濃縮的⼤麻萃取物，可能含⾼濃度四氫⼤麻酚 (It contains concentrated cannabis extract and may have a high THC concentration)

• ⼤麻素 (Cannabinoids ) • 與⼤麻素接受器交替作用的分⼦，包括 1) 超過100種自然產⽣的化學物質或植物性⼤

麻素，包含四氫⼤麻酚及少量⼤麻⼆酚，2) 內源性⼤麻素在體內製造且與⼤麻素接受器結合，3) 合成⼤麻素在實驗室製造，與植物性⼤麻素或內⽣⼤麻素類似 (Molecules that interact with cannabinoid receptors. There are over 100 naturally occurring chemicals or phytocannabinoids including THC and CBD. Endocannabinoids are produced in the body and target the receptors. Synthetic

cannabinoids are produced in the laboratory and mimic the phyto- or endocannabinoids)

Samanta D. Pediatr Neurol 2019; 96: 24-29

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熱帶⼤麻 vs 印度⼤麻

Cannabis Sativa vs Cannabis Indica

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Cannabis Sativa

• Origin • Equatorial climates such as Thailand, southern Africa, and Mexico

• Cultivation • 60-90 days to flower, good for outdoor grows in warm climates

• Plant features

• Tall, slim plants

• Long, thin, light green leaves

• Bud features • Lighter weight with subtle fruity aromas, sometimes hints of red and orange

• Treats • Creative blocks, lack of focus, depression, fatigue

• Popular Stains

Cannabis Indica

• Origin • Mostly central Asia and the Indian subcontinent

• Cultivation • 45-60 days to flower, higher yields, good for indoor grows

• Plant features

• Short, sturdy, and bushy plants

• Short, wide, dark green leaves

• Bud features

• Dense with pungent aromas, sometimes purple

• Treats • Insomnia, chronic pain, anxiety, loss of appetite

• Popular Stains

熱帶⼤麻 vs 印度⼤麻

Cannabis Sativa vs Cannabis Indica

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熱帶⼤麻 vs 印度⼤麻

Cannabis Sativa vs Cannabis Indica

Cannabis Sativa

• 中樞神經系統 high (Head high)

• 刺激 (Stimulating)

• 白天使用 (Daytime use)

• 警覺 (Alertness)

• 振奮及欣快感 (Uplifting and euphoria)

• 創造⼒ (Creativity)

• 緩解憂鬱 (Ease depression)

• 促進活⼒ (Boosts energy)

• ⾼CBD含量 (High CBD level)

Cannabis Indica

• 身體 high (Body high)

• 放鬆 (Relaxing)

• 夜間使用 (Nighttime use)

• 可做為鎮靜劑 (Acts as a sedative)

• 緩解疼痛 (Relives pain)

• 刺激食慾 (Stimulates appetite)

• 幫助睡眠 (Sleep aid)

• ⾼THC含量 (High THC level)

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主要植物性⼤麻素的化學結構

Chemical structure of the main phytocannabinoids

Δ⁹-THC Δ⁸-THC

CBN CBD

Δ⁹-THCV

CBDV CBG

Δ⁹-THCA CBC

CBDA

Izzo AA et al. Trends Pharmacol Sci 2009;30:515-527; Pisanti S et al. Pharmacol Ther 2017;175:133-150 卓⾶病友會 2020.10.24

西湖渡假村

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主要植物性⼤麻素的化學結構 – 精神植物⼤麻素 -

Chemical structure and key information of the main phytocannabinoids - Psychotropic plant cannabinoids -

Δ⁹-THC

四氫⼤麻酚 Δ⁸-THC CBN

Izzo AA et al. Trends Pharmacol Sci 2009;30:515-527; Pisanti S et al. Pharmacol Ther 2017;175:133-150

• Δ⁹-THC (Δ⁹-Tetrahydrocannabinol) • Δ⁸-THC (Δ⁸-Tetrahydrocannabinol) • CBN (Cannabinol)

• Primary psychotropic ingredient of Cannabis

• Most abundant in drug-type plants

• Partial agonist at CB1 & CB2 receptors

• Activates TRPA1 & PPAR-𝛾

• An artefact resulted from isomerization of Δ⁹-THC

• Minuscule in Cannabis

• A product of Δ⁹-THC oxidation

• Weak CB1 agonist and CB2 partial agonist

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主要植物⼤麻素的化學結構 – 非精神(非中毒)植物⼤麻素 -

Chemical structure and key information of the main phytocannabinoids - Non-Psychotropic (non-intoxicating) plant cannabinoids -

⼤麻⼆酚CBD Δ⁹-THCV CBG

• CBD (Cannabidiol) • Δ⁹-THCV (Δ⁹-Tetrahydrocannabivarin) • CBG (Cannabigerol)

• A major non-psychotropic cannabinoid

• Most abundant in fiber-type plants

• Not specific antagonist of CB1 & CB2

• Inhibitor of AEA uptake metabolism

• Abundant in Pakistani hashish

• Δ⁹-THCV antagonizes Δ⁹-THC at low dose (< 3mg/kg)

• As a CB1 agonist at greater doses (10 mg/kg)

• A potent TRPM8 antagonist

• TRPA1, TRPV1 and CB agonist

• AEA reuptake inhibitor

AEA: anandamide

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主要植物⼤麻素的化學結構 – 非精神(非中毒)植物⼤麻素 -

Chemical structure and key information of the main phytocannabinoids - Non-Psychotropic (non-intoxicating) plant cannabinoids -

CBDV

CBC Δ⁹-THCA

CBDA

• CBDV

(Cannabidivarin) • CBC

(Cannabichromene ) • Δ⁹-THCA

(Δ⁹-Tetrahydrocannabinolic acid) • CBDA

(Cannabidolic acid)

• Unknown mechanism • CBC with Δ⁹-THC, the major cannabinoid in freshly harvested dry-type material

• CBC is ~ 2.5 X more toxic than Δ⁹-THC

• Potential TRPA1 agonist

• Inhibitor of AEA reuptake

• Δ⁹-THC has 2 acidic analogs:

Δ⁹-THCA A and Δ⁹-THCA B

• Δ⁹-THCA is a potent TRPA1 agonist and TRPM8 antagonist

• CBDA is the main component of glandular hairs (up to 15%)

• Selective inhibitor of COX2

• TRPA1 and TRPV1 agonist

• TRPM8 antagonist

AEA: anandamide

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非精神(非中毒)植物性⼤麻素的分⼦機轉

Proposed molecular mechanisms of the actions of non-psychotropic (non-intoxicating) phytocannabinoids

• Phytocannabinoids • Mechanism • Pharmacological relevance

• CBD • Antagonist of CB1/CB2 agonists • Antispasmodic effects

• CB2 inverse agonist • Anti-inflammatory effects

• FAAH inhibition • Reduce FAAH expression in the inflamed intestine

• Anandamide reuptake inhibitor • To be determined

• GPR55 antagonist • To be determined

• Positive allosteric modulator at ⍺1 and ⍺1β glycine receptor • Relief chronic pain after inflammation or nerve injury

• μ opioid receptor ligand • To be determined

• Positive allosteric modulator at μ and 𝛿 opioid receptors • The effects occurs at very high concentrations

• TRPA1 agonist • Analgesic effects

• TRPM8 antagonist • Analgesic effects

• TRPV1 agonist • Antipsychotic and analgesic effects

• TRPV2 agonist • The effect is shared by Δ⁹-THC and CBN

• Adenosine uptake competitive inhibitor • Anti-inflammatory effects

• PPAR𝛾 agonist • Vasorelaxation and fibroblast stimulation

• 5-HT1A agonist • Antischemic and anxiolytic properties

• Antagonist of the putative abnormal-CBD receptor • CBD attenuates the vasodilator response to anandamide

• Regulator of intracellular [Ca2+] • Neuroprotective and antiepilepticproperties

• T-type Ca2+ channel inhibitor • Nociception and antiepilepticeffects

• Suppression of tryptophan degradation • Role in pain, inflammation and depression

• 5-Lipoxygenase inhibitor • CBD decreases 5-lipoxygenase in tumor tissues

• 15-Lipoxygenase inhibitor • Anti-atherosclerosis

• Phospholipase Az modulator • Anti-inflammatory effects

Izzo AA et al. Trends Pharmacol Sci 2009;30:515-527 卓⾶病友會 2020.10.24 西湖渡假村

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非精神(非中毒)植物⼤麻素的分⼦機轉

Proposed molecular mechanisms of the actions of non-psychotropic (non-intoxicating) phytocannabinoids

• Phytocannabinoids • Mechanism • Pharmacological relevance

• Δ⁹-THCV • CB1 antagonist • Increases central inhibitory neurotransmission – with a therapeutic potential in epilepsy

• CB2 partial agonist • Stimulates mesenchymal stem cells

• CBG • CB1 and CB2 partial agonist • To be determined

• TRPA1 agonist • Analgesia

• TRPV1 agonist • Analgesia

• TRPM8 antagonist • Analgesia and treatment of prostate carcinoma

• Phospholipase A2 modulator • CBG reduces PGE2 release in human synovial cells

• CBC • TRPA1 agonist • Analgesia

• Δ⁹-THCA • TRPA1 partial agonist • Analgesia

• TRPM8 antagonist • Analgesia

• CBDA • TRPA1 partial agonist • Analgesia

• TRPV1 agonist • Analgesia

• TRPM8 antagonist • Analgesia

• COX-2 inhibitor • To be determined

Izzo AA et al. Trends Pharmacol Sci 2009;30:515-527 卓⾶病友會 2020.10.24 西湖渡假村

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⼤麻⼆酚治療⼈類疾病的作用機轉

Mechanism of action of cannabidiol (CBD) for human diseases

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⼤麻⼆酚 (CBD; cannabidiol ) Cannabidiol (CBD)

• A major non-psychotropic (non-intoxicating) cannabinoid

• 1940, first isolated by Adams and coworkers

• 1963, structure and stereochemistry determined by Mechoulam and Shvo

Izzo AA et al. Trends Pharmacol Sci 2009;30:515-527; Atalay S et al. Antioxidants 2020;9:21

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⼤麻⼆酚 (CBD; cannabidiol ) 在細胞膜接受器上的主要作用 Major effects of CBD on several membrane receptors

• AEA, anandamide; 2-AG, 2-arachidonoylglycerol; FAAH, fatty acid amide hydrolase; AMT, AEA membrane transporter; ROS, reactive oxygen species;

Ub, ubiquitin; p65, transcription factor NF-κB; Nrf2, nuclear factor erythroid 2-related factor 2; ARE, antioxidant response elements.

• Blue arrows indicate agonist activity; red arrows indicate antagonist activity; dashed blue arrows indicate weakly agonistic activity;

green arrows indicate endocannabinoid agonist activity; grey arrows indicate chemical and biological effects Atalay S et al. Antioxidants 2020;9:21 卓⾶病友會 2020.10.24

西湖渡假村

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⼤麻⼆酚 (CBD; cannabidiol ) 具直接抗氧化作用 Direct antioxidant effects of CBD

• Closed arrows indicate reducing effects

• Opened arrows indicate inducing action

Atalay S et al. Antioxidants 2020;9:21 卓⾶病友會 2020.10.24

西湖渡假村

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⼤麻⼆酚 (CBD; cannabidiol ) 具間接抗氧化及抗發炎作用 Indirect antioxidant and anti-inflammatory effects of CBD

• Closed arrows indicate inhibition

• Opened arrows indicate activation

Atalay S et al. Antioxidants 2020;9:21

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⼤麻⼆酚 (CBD; cannabidiol ) 的多面向藥理作用 Multifaceted pharmacological effects of CBD

Pisanti S et al. Pharmacol Ther 2017;175:133-150

CBD

Neuro- protective

Relieves pain

Relieves anxiety

Anti- depressant Causes

vasorelexation Anti-

oxidant Reduces cancer

cell growth Reduces tumoral angiogenic

process

Reduces

inflammation 緩解疼痛

緩解焦慮

抗憂鬱

抗氧化⾎管放鬆減少腫瘤細胞⽣長

減少腫瘤⾎管⽣成過程

減少發炎

神經保護

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⼤麻⼆酚 (CBD; cannabidiol ) 的藥理作用 CBD pharmacological effects

中樞神經系統 (CNS)

• 阿茲海默症 (Alzheimer’s disease)

• 帕⾦森⽒症 (Parkinson’s disease)

• 多發性硬化症 (Multiple sclerosis)

• 癲癇 (Epilepsy)

• 亨丁頓舞蹈症 (Huntington’s disease)

• 缺⾎缺氧傷害 (Hypoxia-ischemic injury)

• 疼痛 (Pain)

• 焦慮 (Anxiety)

• 憂鬱 (Depression)

中樞神經系統以外 (Extra-CNS)

• 腫瘤 (Cancer)

• 噁⼼ (Nausea)

• 發炎疾病 (Inflammatory diseases)

• 風濕性關節炎 (Rheumatoid arthritis)

• 感染 (Infection)

• 發炎性腸症 (Inflammatory bowel and Chron’s disease)

• ⼼⾎管疾病 (Cardiovascular diseases)

• 糖尿病併發症 (Diabetes complications)

Pisanti S et al. Pharmacol Ther 2017;175:133-150

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⼤麻⼆酚治療癲癇的可能作用機轉

Proposed mechanism of action of CBD in epilepsy

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⼤麻⼆酚 (CBD; cannabidiol ) 具間接抗氧化及抗發炎作用 Indirect antioxidant and anti-inflammatory effects of CBD

• Closed arrows indicate inhibition

• Opened arrows indicate activation

Atalay S et al. Antioxidants 2020;9:21

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⼤麻素在神經疾病中會影響GABA

Cannabinoids on Neurological Diseases with GABA Involvement

Cifelli P et al. Int J Mol Sci 2020;21:723 卓⾶病友會 2020.10.24

西湖渡假村

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⼤麻⼆酚治療癲癇的多模式可能作用機轉

Proposed multimodal mechanism of action of CBD in epilepsy

Gray RA and Whalley BJ. Epileptic Disord 2020; 22 (Suppl 1): S10-S15 卓⾶病友會 2020.10.24

西湖渡假村

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非精神(非中毒)⼤麻素的藥理作用

Pharmacological actions of non-psychotropic (non-intoxicating) cannabinoids

Izzo AA et al. Trends Pharmacol Sci 2009;30:515-527

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⼤麻⼆酚 (CBD; cannabidiol ) 的製造、合成、代謝及藥物動⼒學特點

CBD production, biosynthesis, metabolism, and pharmacokinetic characteristics

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⼤麻⼆酚 (CBD; cannabidiol ) 的製造、合成、代謝 CBD production, biosynthesis, and metabolism

Russo EB. Trends Pharmacol Sci 2017;38:198-201 卓⾶病友會 2020.10.24

西湖渡假村

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⼤麻⼆酚 (CBD; cannabidiol ) 的藥物動⼒學特點 Pharmacokinetic characteristics of CBD

Landmark CJ and Brandl U. Epileptic Disord 2020; 22(Suppl):S16-S22

Pharmacokinetic properties Comments Absorption • Bioavailability ~ 6%

• T_max 90-120 min

• Oral oil formulation

• Minimal absorption

• Extensive first-pass metabolism through CYP3A4

• Substantial variability between patients, > 4-5-fold with a fat-rich meal Distribution • Protein binding 94-99%

• Vd 20-40.000 L!

• Variability in free fraction?

• Displacement in interactions ? Metabolism • CYP3A4, CYP2C19

• UGT1A7, UGT1A9, UGT2B7

• t_1/2 24-60h

• Strong enzyme-inhibiting properties, PGP? Active metabolite, 7-OH-CBD

Excretion • Faeces, urine

• Unchanged 12%

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Drug interaction

• Additive ( 1+ 1 =2)

• Synergistic ( 1+ 1 > 2)

• Antagonistic ( 1 + 1 < 2)

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⼤麻⼆酚 (CBD; cannabidiol ) 的代謝 Metabolism of CBD

• 7-hydroxy-CBD (7-OH-CBD) is an active metabolite

• Carboxylic acid (7-OOH-CBD) is regarded as an inactive metabolite

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⼤麻⼆酚與抗癲癇藥物的藥物動⼒學交替作用 Pharmacokinetic interactions with AEDs

CL: clearance

• 癲通

• 癲能停

• (除癲達)

• (苯巴比妥)

• 帝拔癲

• 除癲達

• 司替戊醇

• 樂命達

• 福利寕

• 癲控達

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抗癲癇藥物與⼤麻⼆酚的藥物動⼒學交替作用 Pharmacokinetic interactions with CBD

• ⼤麻⼆酚加上帝拔癲可能會使肝功能上升

• ⼤麻⼆酚加上福利寕會使福利

寕活性代謝產物濃度上升5倍

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藥物間的交替作用 Potential drug interactions

Samanta D. Pediatr Neurol 2019; 96: 24-29

Enzyme Substrates Drug-drug interaction

• Moderate or strong inhibitor

of CYP3A4 or CYP2C19 • Amiodarone, Erythromycin,

Fluconazole, Verapamil (維帕特), etc • These can increase CBD plasma concentration

• Strong CYP3A4 or CYP2C19

inducer • Rifampicine • These can decrease CBD plasma concentration

• Substrates of UGT1A9 • Diflunisal, Propofol, Fenofibrate • CBD can inhibit the enzyme activity and increase the concentration of dosage of substrates

• Substrates of UGT2B7 • Gemfibrozil, Lamotrigine (樂命達),

Morphine, Lorazepam • CBD may inhibit the enzyme activity and increase the concentration of dosage of substrates

• Clobazam • Level of the active metabolite of clobazam (N-

desmethylclobazam) may increase by 5 fold, a potential for added benefit with an increased risk of side effects

• Substrates of CYP2C8 • Montelukast • CBD may inhibit the enzyme activity and increase the concentration of the substrates

• Substrates of CYP2C9 • Phenytoin (癲能停) • CBD may inhibit the enzyme and increase the concentration of the substrates

• Substrates of CYP1A2 • Theophylline, Caffeine • CBD may induce or inhibit the enzyme activity, and increase or decrease of the dosage may be necessary

• Substrates of CYP2B6 • Bupropion, Efavirenz • CBD may induce or inhibit the enzyme activity, and increase or decrease of the dosage may be necessary

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⼤麻⼆酚與常用抗癲癇藥物間的交替作用

Interactions between cannabidiol and commonly used AED

CBD AED

• 兒童及成⼈增加⼤麻⼆酚劑量

(↑ CBD dose in children and adults) • 增加妥泰濃度 ; ↑ [Topiramate]

• 增加克雷格濃度; ↑ [Rufinamide]

• 增加福利寕代謝產物濃度; ↑ [N-des-methylclobazam]

• 降低福利寕濃度;↓[Clobazam]

• 成⼈增加⼤麻⼆酚劑量

(↑ CBD dose in adults) • 增加左能安濃度; ↑ [Zonisamide]

• 增加艾司利卡西平濃度; ↑ [Eslicarbazepine]

• ⼤麻⼆酚加上帝拔癲

(CBD + Valproate) • 肝臟酵素上升

(Higher AST and ALT levels)

Gaston TE et al. Epilepsia 2017;58:1586-1592

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⼤麻⼆酚劑量依賴的療效 Dose dependency of efficacy

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市售藥用⼤麻⼆酚 CBD in the market

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Cannabidiol (Epidiolex)

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Cannabidiol (Epidiolex), Quick facts

• FDA適應症：用於⼤於或等於2歲的卓⾶症候群及克雷格症候群病⼈

(FDA-approved indications: treatment of seizures in patients ≥ 2 years of age with Dravet sx or Lennox-Gastaut sx)

• 屬5級管制藥品：DEA US (drug enforcement Administration) schedule: V

• 每cc有100毫克，每瓶100cc，草莓⼝味。Dosage form: 100 mg/ml oral solution (strawberry flavored)

• 劑量Dosing: initial 2.5 mg/kg twice daily (5 mg/kg/d), titrated at weekly intervals to minimum effective dose or 10 mg/kg twice daily (20 mg/kg/d)

• 肝功能異常者需調整劑量 (Dosage adjustment needed in hepatic impairment)

• 不要突然停藥 (Do not abruptly discontinue)

• 可以空腹或與食物⼀起服用 (Administration: administer consistently with or without food)

• 主要藥物交替作用包括福利寕、帝拔癲、 CYP3A4 & CYP2C19 誘導及抑制劑、中樞神經系統抑制劑

(Primary drug-drug interactions: clobazam, valproates, CYP3A4 & CYP2C19 inducers & inhibitors, CNS depressants)

• 常見不良反應包括失眠、腹瀉、食慾降低及肝功能指數上升

(Common adverse events: somnolence, diarrhea, decreased appetite, elevated hepatic transaminases)

• 吃藥前需驗肝功能指數及黃疸值，並在開始吃藥後第1, 3, 6 個月監測肝指數及黃疸值

(Monitoring: AST/ALT and total bilirubin at baseline and 1, 3, and 6 months after initiation and 1 month following dosing changes and/or addition of medications affecting liver function

• Product distribution: available via limited distribution (i.e., specialty pharmacy)

• Manufacturer’s estimated annual list price: USD 32,500

Chen JW et al. Ann Pharmacother 2019;53:603-611

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Clinical handling of CBD

• Start low (2.5 or 5 mg/kg/day), increase to 10mg/kg after 2 weeks

• Review clinical response and adverse effects on 10 mg/kg/day

• Remain on this dose if effective

• Otherwise increase dose in steps of 5 mg/kg/fay if CBD is well tolerated

• Stop at 20-25 mg/kg/day – withdraw CBD if ineffective

Landmark CJ and Brandl U. Epileptic Disord 2020; 22(Suppl):S16-S22 卓⾶病友會 2020.10.24

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肝功能異常

Hepatic impairment

肝功能異常

(Hepatic impairment) 起始劑量

(Starting dose) 維持劑量

(Maintenance dose) 最⼤建議劑量 (Maximum recommended dose)

輕度 (Mild) 2.5 mg/kg BID

(5 mg/kg/day) 5 mg/kg twice daily

(10 mg/kg/day) 10 mg/kg twice daily (20 mg/kg/day)

中度 (Moderate) 1.25 mg/kg BID

(2.5 mg/kg/day) 2.5 mg/kg BID

(5 mg/kg/day) 5 mg/kg BID (10 mg/kg/day) 重度 (Severe) 0.5 mg/kg BID

(1 mg/kg/day) 1 mg/kg BID

(2 mg/kg/day) 2 mg/kg BID (4 mg/kg/day)*

* Higher doses of cannabidiol may be considered in patients with severe hepatic impairment where the potential benefits outweigh the risks

(41)

不良反應 (Tabulated list of adverse reactions)

System Organ Class Frequency Adverse reactions from clinical trials

• 感染 (Infections and infestations) • 常見 (Common) • 肺炎氣管炎鼻咽炎泌尿道感染 (Pneumonia, bronchitis, nasopharyngitis, urinary tract infection)

• 代謝及營養障礙 (Metabolism and

nutrition disorders) • 非常常見 (Very common)

• 常見 (Common) • 食慾降低 (Decreased appetite)

• 食慾增加 (Increased appetite)

• 精神疾病 (Psychiatric disorders) • 常見 (Common ) • 躁動、失眠、異常⾏為、攻擊性、異常⾏為

Irritability, insomnia, aggression, abnormal behaviour, agitation

• 神經系統疾病 (Nervous system disorders) • 非常常見 (Very common)

• 常見 (Common) • 失眠 Somnolence

• 想睡、流⼝⽔、顫抖 Lethargy, drooling, tremor

• 呼吸胸腔及橫膈膜疾病 (Respiratory,

thoracic and mediastinal disorders) • 常見 (Common) • 咳嗽 Cough

• 腸胃道疾病 (Gastrointestinal disorders) • 非常常見 (Very common) • 腹瀉、嘔吐 (Diarrhoea, vomiting)

• 肝膽疾病 (Hepatobiliary disorders) • 常見 (Common) • 肝功能指數上升 (AST increased, ALT increased, GGT increased, liver function test abnormal)

• 皮膚及皮下組織疾病 (Skin and

subcutaneous tissue disorders) • 常見 (Common) • 皮疹 (Rash)

• 全身疾病 (General disorders and

administration site conditions) • 非常常見 (Very common) • 發熱、疲倦 (Pyrexia, fatigue)

• 調查 (Investigations) • 常見 (Common) • 體重減輕 (Weight decreased)

• 非常常見 Very common (≧1/10),常見common (≧ 1/100 to < 1/10), 不常見uncommon (≧ 1/1,000 to < 1/100)

(42)

⼤麻⼆酚申請流程

Application process for CBD

(43)

CBD

藥名商品名藥廠 Approval 代理商價錢

Cannabidiol

(medical) Epidyolex^®

(Europe) GW Pharma Limited EMA Giddi Pharma C o., Ltd.

(吉帝藥品股份有限公司) NTD 1,000/ml (100mg) Cannabidiol

(medical) Epidiolex^®

(USA) GW Pharma Limited FDA

Approves Tian Shing Trading Co.,Ltd

(天⾏貿易股份有限公司) NTD 1,000/ml (100mg) Cannabidiol

(medical) 國嘉製藥⼯業股份有

限公司 CE BioInc

(昭羿⽣醫科技有限公司) NTD 150/ml (100mg) Cannabidiol

(edible) Hempsvision Harrens Lab Inc Markvision Biotech, INC. NTD 64.5/100mg

(44)

Epidyolex

^{® /}

Epidiolex

^®

專案進⼝流程

流程

Step 1 使用單位向醫院IRB申請「⼈體研究倫理審查委員會核准申請特定藥物使用之證明」

Step 2 使用單位向食藥署管制藥品組申請「專案進⼝同意函」

依據特定藥物專案核准製造及輸⼊辦法第2條，區域醫院以上之教學醫院向中央衛⽣主管機關申請特定藥物之專案輸⼊，須檢附：

1. 醫院診斷書

2. 申請醫院之⼈體研究倫理審查委員會核准申請特定藥物使用之證明 3. 完整治療計畫書及相關⽂獻依據

4. 病⼈同意書

5. 所需藥物數量及計算依據 6. 藥物之說明書

7. 藥物之國外上市證明或各國醫藥品及收載影本

Step 3 使用單位向食藥署管制藥品製藥⼯廠辦理「第⼆級管制藥品之專案輸⼊」

依據食藥署管制藥品製藥⼯廠代輸⼊第⼀、⼆級管制藥品作業⽅式，須檢附：

1. 食藥署核准之藥品「專案進⼝同意函」

2. 「管制藥品專案輸⼊申請書」

3. 「訂購單」

4. 「醫院委託廠商之委託書」

Step 4 藥品輸⼊台灣後食藥署會通知使用單位⾄食藥署管制藥品製藥⼯廠門市櫃台辦理「繳款及提貨⼿續」

依據「食藥署管制藥品製藥⼯廠代輸⼊第⼀、⼆級管制藥品作業⽅式」，提貨時需繳交：

1. 報關費：依照實際支出情形收取 2. 倉租：依照實際支出情形收取 3. ⼿續費：每件代輸⼊案5000元

(45)

國內CBD專案製造申請流程

醫師提出用藥需求藥委會

TFDA申請專案製造

醫院

專案製造核准函藥廠製造

發函同意

審查同意

正本

副本供應

(46)

國內CBD專案製造申請流程

醫院藥商/藥廠

科部提藥 1. 病患同意書

2. 治療計畫書

3. 由科部向藥委會提出藥物需求

1. 提供報價 2. 提供藥品仿單

3. 提供國外上市證明(處⽅依據)

藥委會審查 1. 計算醫院年需求量

2. 藥委會審查同意函+同意書+治療計畫書+年需求量+廠商提供資料(仿單+處⽅依據)向TFDA 發函申請專案製造

3. 說明：依據藥事法48條之2地1項第2款，為診治嚴重失能疾病，且國內尚無適當藥物或合適替代療法，提出「特定藥物專案技術核准製造」

1. 簽訂專案製造合約書

TFDA核准函 1. 發給核准函 1. 發給核准函

用藥追蹤 1. 記錄副作用、療效、通報不良反應

2. 以real word data 作為臨床資料，供TFDA審查藥品登記之用

1. 依核准函製造藥品

2. 產製藥品依申請數量供應醫院，不得出售他用或轉讓他用

3. 長期使用要辦理查驗登記，須要彙整使用經驗與療效結果作為臨床資料

(47)

藥用⼤麻中之⼤麻⼆酚 Cannabidiol in Medical Marijuana