RHEUMTOID ARTHRITIS

台中榮民總醫院
臨床藥學科
鄭鴻基主任
 前言 -1
 類風濕性關節炎﹙ Rheumatoid
Arthritis ， RA﹚ 是一種慢性的全身性
、發炎性的自體免疫疾病。而所謂自體
免疫疾病，就是病人本身免疫系統的功
能過度活躍，導致不但會攻擊外來的異
物，也會去侵犯自身的正常的組織器官
而產生自體組織器官的損傷。
 前言 -2
 特徵：無化膿性增生性滑膜炎，經過一段時間
後會導致關節軟骨破壞，及漸進破壞性關節炎。
另外也會侵犯全身各個組織器官，使病患的活
動受阻礙，甚至最後必須藉助別人的幫助才能
維持正常作息。 RA 至目前 止仍無法完全治
癒。因此，對於 RA 病人成功的處理方法，除
了需要對疾病的病理、生理及進展過程有正確
的認知外，還需確認個別的治療目標，了解不
同的治療方式及其潛在的效力和毒性。
 流行病學
目前全球大約有 1﹪~2﹪ 的人口患此
疾病。然而 RA 並不是老人的專利，
它可以在任何年齡出現，約有 70﹪
的病人是介於 30 至 60 歲之間，而
以 40 歲為其高峰。一般而言女性與
男性的罹患比例是 3 ： 1 ，但是這
種差異在年老者並不存在。而台灣
每千人有四人罹患類風濕性關節炎
，其中以生育年齡的女性最易發生
RA 的流行病學
英國 1990-1991 年男性和女性類風濕性關節
炎
USA -Art hri ti s
1985 - 3 千 5 百萬 關節炎病
患
1995 - 4 千萬 關節炎病患
2020 - 5 千 9 百萬 關節炎病
患

第二大無法就業原因
估計每年對經濟影響有 650
億美元
 病理機轉
類風濕性關節炎的病因至今仍然不明，只知其大
概的病理機轉（ Fig1 ）為：當外來的類風濕因
子（ RF ）去刺激滑膜腔內的 macrophage 釋
放出第一介白質（ IL1 ），而刺激 T-
lymphocyte ，使之活化並產生兩條免疫路徑。
其中一條路徑為 ，活化的 T-lymphocyte 會釋放
出化學趨化物質（ chemical mediator ），進
而刺激 macrophage 對 RF 的吞噬作用。另一
路徑 ，活化的 T-lymphocyte 會釋放出第二介
白質（ IL2 ），進而產生一連串的發炎反應，
最後導致軟骨關節的破壞。
Figure 1F. A working classification of chronic
polyarthritis.

A working classification of chronic polyarthritis. It is

important to classify each patient because of differences in
prognosis between the various syndromes. RF+, RF , and
RF± refer to results of tests for IgM rheumatoid factor. Adult
juvenile rheumatoid arthritis (AJRA) and remitting
seronegative symmetrical synovitis with pitting edema
(RS3PE) are examples of subsets of seronegative
polyarthritis (SP). Nodules, vasculitis, sicca syndrome, and
Felty syndrome may develop in subsets of patients with
rheumatoid arthritis (RA). Palindromic rheumatism (PR),
nodulosis (N), and seronegative symmetric synovitis of the
wrists (S3) are recognizable syndromes included in the
ambiguous category of RF±.
DIAGNOSIS > Rheumatoid Arthritis

Approximately 80% of adult patients with

chronic polyarthritis treated at referral
center clinics are consistently RF+. Most
develop radiographic evidence of bony
erosions within the first 2 years of disease
(Figure 2). Subsets of this group develop
extra-articular features as well, such as
nodules (Figure 3), vasculitis, sicca
features, and Felty syndrome.
Figure 2. Radiograph of
right hand showing bony
erosions.

Radiograph of right hand showing

bony erosions at the proximal
interphalangeal and
metacarpophalangeal joints.
（ Fig4 ）： PIP erosion 與 MCP erosion 的位置圖。
Figure 3. Flexion
deformities in
rheumatoid arthritis.

Flexion deformities in
rheumatoid arthritis.
Rheumatoid nodules have
developed at sites of
trauma over the proximal
interphalangeal joints of the
third and fourth fingers.
Figure 4. Joint damage is both
irreversible and cumulative.
Joint damage is both irreversible and
cumulative. Although inflammation often
gradually subsides over time it does not
go away completely.
Irreversible loss of function due to
structural damage to cartilage,
bone, tendon, and capsule is
cumulative (damage =
inflammation X intensity X
time). Irreversible damage can
occur relatively rapidly (in several
months).
Table 3. Remission of rheumatoid arthritis*
1. Duration of morning stiffness <15 min

2. No fatigue

3. No joint pain

4. No joint tenderness or pain on motion

5. No swelling in joints or tendon sheaths

6. ESR <30 mm/h for women, <20 mm/h for men

*
American College of Rheumatology definition. Five of six criteria must exist for at
least 2 months.
ESR erythrocyte sedimentation rate.
 緩解期 的徵 兆
類風濕性關節炎是種慢性疾病。
美國風濕病學學會 (ACR) 對類風濕性關節炎之緩解所
下的定義，可參考下列的徵兆。如果你在至少連續二
個月的期間內，出現了以下所述五種以上的徵兆，那
麼這就可能指出你的類風濕性關節炎正處於緩解期：
‧ 早上時關節感到僵硬，但持續不到十五分鐘
‧ 不會有疲倦感
‧ 關節並不會疼痛
‧ 關炎無觸痛感或移動時不會感到疼痛
‧ 關節或 肌腱鞘 等處 並無軟 組織 腫脹的 情形
‧ 女性紅血球沈降速率 (ESR) 小於
30mm/hr ，而男性小於 20mm/hr
 類風濕性關節炎的診斷標準為
何？

 人常會將 類風濕性關節炎和風濕性
關節炎 混為一談，其實這是兩種不
同的疾病。因為風濕性關節炎發病
通常是急劇的，關節紅腫疼痛得厲
害；類風濕性關節炎 大多發病緩慢，
關節 不會紅腫 但呈 腫脹 僵硬、多 發
性，同時病因不明。
 類風濕性關節炎的診斷標準為
何？
 類風濕性關節炎是屬於一種關節炎症為主的慢性
反覆發作的全身性疾病。初期時，關節會疼痛、
腫脹和功能有障礙，和風濕性關節炎一樣；但晚
期時關 節會僵 硬和 畸形， 可能 導致殘 廢。

類風濕性關節炎到目前為止，未發現一定的病因
，病變大致在關節滑膜，其次是槳膜、心臟、肺
部或是皮膚、眼部、血管等組織器官，而且一旦
發病，時輕時重 且多 發性。
 類風濕性關節炎的診斷標準為
何？
 診斷類風濕性關節炎，均是引用美國風濕病學會
制定的標準，其內容如下：
1. 早晨僵硬的時間超過一個小時以上。
2. 醫生觀察到三個或三個以上關節部位的組織
　有腫脹的情況。
3. 手腕、掌指間關節腫脹超過六週。
4. 對稱性關節﹝如身體兩側相同關節﹞同時腫
　脹或先後發病。
5. Ｘ光檢查出手部或手腕關節軟骨周圍骨質稀
　疏改變。
6. 類風濕因子呈陽性。
7. 類風濕結節。
 類風濕性關節炎的診斷標準為
何？

 如果上述情況 1~4 的情況必須持續六週

；
具備以上４種或４種以上的條件，就可以
診斷為類風濕性關節炎。

 若能真正了解此疾病的診斷標準，就可預
防因為醫生或病人誤治或誤診而引起不必
要的後果。
Normal cortical & trabecular bone
 Figure 8. The natural radiographic history of a
pocket erosion.

The natural radiographic history of a pocket

erosion with successful suppression of
inflammation. A, Normal cortical and trabecular
bone. B, The earliest detectable lesion is a
break in the bony cortex followed by C, loss of
spongy bone to produce a pocket erosion.
Rarely, these pockets are filled in with new bone
and disappear. D, Most often, they become
recorticated with the reformed cortical bone
outlining the erosive pocket.
骨關節炎診斷與評估
空間變窄並有骨贅的形成
類風濕性關節炎的診斷與評估
正常和罹患 R Ａ的手部 X 光片
Table 2. The 4 R s: role of the generalist in treatment of rheumatoid
arthritis and seronegative polyarthritis

Refer patient to rheumatologist early before irreversible

damage has occurred

Reinforce the basic program of rest and exercise and monitor

the patients drug program

Return the patient periodically to the rheumatologist for

reassessment of prognosis and treatment program

Review the goals of the therapeutic program with the patient

annually; if goals are not being met consider obtaining a
second opinion
Table 4. Six steps to successful therapy for seropositive
rheumatoid arthritis
1. Accurate diagnosis and prognosis

2. Precise assessment, initial and serial, using clinical,

radiographic, and laboratory variables
3. Explain pathophysiology and basic program to patient

4. Use whatever drugs it takes to control synovitis

5. Monitor serially for drug effectiveness and for side effects

with gradual dose reduction after sustained remission

6. Never completely withdraw therapy from a patient in

remission
Pyramidal schema of the treatment of
RA

Surgery Experimental Local

corticosteroid
Cytotoxic therapy injections

Systemic corticosteroids
Slow-acting
anti-inflammatory drugs
Fast-acting non-steroidal
anti-inflammatory drugs
Education, counseling, physical
therapy, changes in lifestyle
Sawtooth Paradigm
Strategies of combining antirheumatic
Step-down bridge drug Step-up

Time Time

Overlap and Switch Parallet

Time Time
NSAIDs
NSAID-Gastropathy: U.S. Mortality Data for
Several Selected Disorders in 1997
25,000

Wolfe et al. N Engl J Med 1999;340:1888-1899

20,197
20,000
16,685 16,500
15,000
=33
No. of Deaths

10,503
10,000

5,338
4,441
5,000
1,437
0
ia ity a a r se
m ID
s ic lom m nce a
ke A ox
T ye sth
Ca is e
L eu I M A
ca
l s D
D
G
iple vi in'
A I lt er g k
NS Mu C
Ho
d
Cause of Death
 一般常用的 NSAIDS
商品 名 化學 名稱 製造廠
Relifex nabumetone 美占史克
Voltaren diclofenac 汽巴嘉基
Naprosyn naproxen 中化
Brufen ibuprofen Kaken
Cinopal fenbufen 氰胺
Indocid indomethacin 默克
Profenid ketoprofen Rhone-poulenc
Surgam tiaprofenic acid 龍壽 / 赫斯特
Tilcotil tenoxicam 羅氏
Feldene piroxicam Pfizer
Mobic Meloxicam 百靈佳
 Mechanism of Action of NSAIDs:
Current Hypothesis
CO2H

Arachidonic acid

COX-1
COX-2
“Constitutive”
(Housekeeping enzyme) NSAIDs “Inducible”

Prostaglandins Kidney
Prostaglandins
& Brain

Protection of Mediate pain,

Hemostasis
gastric mucosa inflammation and fever
 Selective vs Specific
COX-1 Equipotent for COX-2 COX-2
Selective COX-1 and COX-2 Selective Specific
(Ratio > 1) (Ratio = 1) (Ratio < 1) (Ratio< < 1)

Aspirin Etodolac Celecoxib

Nabumetone
Indometha Meloxica ~1/400
cin m* Rofecoxib
Sulindac (VIOXX)
Nimesulid ~1/1000
Piroxicam e**
Naproxen
Diclofenac *Meloxicam
Boerhinger-
Ibuprofen Ingelheim
**Nimesulide
Various
 efficacy
NSAIDs WHY SO
MANY ? safety

carboxilic
pyrazolones Nabumetone oxicams
acids

Piroxicam
BUTAZOLIDIN Propionic Acetic Anthranilic Meloxicam

Salicylic
ASPIRIN 1898 Indoleacetic acid pyrolacetic acid
DOLOBID Indomethacin Tolmetin
Ibuprofen Sulindac
Ketoprofen Etodolac
non-acetyl Mefenamic
Naproxen
TRILISATE acid
DISALCID
phenylacetic acid Diclofenac
 Hypothesis
COX-2 Specific Inhibitors
will be anti-inflammatory and
analgesic without the
typical side effects
of NSAIDs.

10/17/08
 Prostaglandins and Renal Function
 The relative roles and importance of
COX-1 and COX-2 in the kidney are not
well understood.
 The deleterious renal effects of NSAIDs
in patients at risk are well established.
 The renal profile of each COX-2 inhibitor,
approved or investigational, has yet to be
fully established.
 Goals of Arthritis Therapy
Achieved by
conventional
Goal NSAIDs

Relieve pain/inflammation yes

Minimize risk of therapy no
Retard disease progression no
Prevent work disability unknown
Enhance quality of life and
functional independence yes/no
 Two Forms of Cyclooxygenase
Cyclooxygenase-1 (COX-1)
• Produces prostanoids
that mediate homeostatic
functions
• Constitutively expressed
• Especially important in:
– Gastric mucosa; small
and large bowel mucosa
– Kidney
– Platelets
– Vascular endothelium
DuBois et al. FASEB J. 1998; 12: 1063–1073
Cyclooxygenase-2 (COX-2)
• Produces prostanoids that
mediate inflammation, pain,
and fever
• Induced mainly at sites of
inflammation by cytokines
• Constitutive expression in:
– Brain
– Kidney (mainly animal data)
Diagrammatic Representations of the COX-1
and COX-2 Structure
As Determined by X-Ray Crystallography

COX-1 COX-2
C-terminal C-terminal
containing containing
active sites active sites
Smaller
valine at
523 opens
Hydrophobic hydrophilic
Hydrophobic “side
channel channel pocket”
Bulky
isoleucine
at position Arginine
523 closes at 120
hydrophilic
“side pocket”
N-terminal Hydrophilic
N-terminal
Arginine “side pocket”
at 120

Kurumbail et al. Nature. 1996; 384: 644-648

COX / Substrate Interaction

COX-1
C-terminal
containing
active sites

d PG
ci
A
ic
on
id
ch
ra
A

Arginine
at 120

N-terminal

Kurumbail et al. Nature. 1996; 384: 644-648

 Classical NSAID: Non-specific binding
to COX-1 and COX-2
Terminal Carboxylic Acid Plays an Important Role
COX-1 COX-2
NSAID NSAID
(flurbiprofen) C-terminal (flurbiprofen)
phenyl group containing phenyl group C-terminal
binds to active sites binds to containing
hydrophobic hydrophobic active sites
channel channel

Carboxylic
group
of NSAID
Carboxylic
forms
group
c id “salt
cA
of NSAID
c id bridge”
o ni forms
i cA with
d n
c hi “salt bridge”
do Arginine
a with hi
Ar a c at 120
N-terminal
Arginine Ar
at 120
N-terminal

Kurumbail et al. Nature. 1996; 384: 644-648

 Celecoxib:
A “Purpose Designed” Specific COX-2
Inhibitor

Polar sulfonamide NH 2
group to bind
to hydrophilic O S
“side pocket” O

N
N No terminal acid
CF 3
group to bind to
Arg120 in COX-
1
Methylphenyl
group to bind to H C
3
hydrophobic channel

Penning et al. J Med Chem. 1997; 40: 1347

 Specific COX-2 Inhibitor Binding to COX-2
Exploitation of the “Side Pocket”
COX-2
C-terminal
Specific COX-2 inhibitor containing
active sites
– phenyl group binds to
hydrophobic channel

Hydrophilic
“side pocket”

Acid
i c
n Arg 120
do
c hi Arg 513,
a
Ar N-terminal Hist 90 – forms hydrogen
bonds with oxygen in
sulfonamide side chain

Kurumbail et al. Nature 1996; 384: 644-648

NSAIDs: Unmet Medical Need
 Widely used for chronic treatment of
arthritis and pain
 Significant side-effects:
 Gastric and intestinal toxicity (serious
events in 2 to 4% per year)
 Decreased renal function in renally
compromised patients
 Reduced platelet function (bleeding
events rare; platelet effects may
contribute to morbidity and mortality of
GI bleeding)
 Pharmacokinetics
Celecoxib
 Absorption
 75% bioavailability
 food enhances bioavailability by 7-20%
 Distribution
 97% bound to plasma proteins
 Protein binding is independent of
drug concentration
 3% unbound with linear kinetic profile

Karim A et al. Pharm Res 1997;14(supp11):S-617.

Data on File: Searle
 Pharmacokinetics
Celecoxib
 Metabolism
 hepatic metabolism by cytochrome
P450 2C9
 inactive metabolites
 Excretion
 57% fecal
 29% of excretion is the carboxylic
acid metabolite in the urine
 <1% unchanged drug in the urine
Karim A et al. Pharm Res 1997;14(supp11):S-617.
Data on File: Searle
 Metabolism of Celecoxib
CF3 CF3

N N
N N
P450 2C9
HOH2 C
H3 C Hydroxylation
Celecoxib Inactive Alcohol
SO2 NH2 Metabolite SO2 NH2

CF3 CF3
Oxidation

N N
N Conjugation N

Glucuronide-OOC HOOC

Glucuronide of the Inactive Acid

SO2 NH2
Acid Metabolite SO2 NH2 Metabolite (major)
(urinary)
Drug-Drug Interactions

No effect on drugs studied:

– Methotrexate
– Lithium
– Glyburide
– Warfarin
– Phenytoin
– Tolbutamide
Incidence of GI Symptoms (>2%)
North American Controlled Arthritis Trials
Celecoxib
Adverse Placebo 100 mg 200 mg 200 mg NSAID
Event BID QD BID
n 1864 1779 453 1914 2098

Abdominal 2.8 3.4 2.0 5.2 8.2†

Pain
Dyspepsia 6.2* 8.7 4.6 9.9 12.0‡
Diarrhea 3.8** 5.0 3.5 6.6 6.1
Nausea 4.2 3.6 2.4 3.7 5.6§
Flatulence 1.0*** 2.1 2.2 2.3 3.7ƒ

* placebo < celecoxib, p=0.004 † celecoxib < NSAID, p=0.21

** placebo < celecoxib, p=0.008 ‡ celecoxib < NSAID, p<0.001
*** placebo < celecoxib, p=0.003 § celecoxib < NSAID, p=0.002
ƒ celecoxib < NSAID, p=0.003
Data on File: Searle
 GI Discomfort
Abdominal Pain, Nausea, or
Cumulative Probability 0.25 Dyspepsia
0.20
NSAIDs
0.15 n=2,427
Celecoxib
n=3,216
0.10 Placebo
n=1,136
0.05

0.00
0 7 14 21 28 35 42 49 56 63 70 77 84
Days

NSAIDs compared to Celecoxib, p<0.01

Placebo compared to Celecoxib, p=NS
Data on File: Searle
 Rate of Severe UGI Events
Patient Years Rate
# of Patients Exposure # of Events (% per year)
NSAIDs 2,768 535 9 1.7%

Celecoxib 6,376 1,020 2 0.2%

50-800mg/day
Placebo 1,864 208 0 –

Open-Label 4,499 5,002 9 0.18%

Celecoxib
Non-Users
Rodriguez et al 16,672 1,000,000 1,012 0.1%
McDonald et al 73,792 220,540 510 0.23%
Gutthann et al 5,770 385,000 385 0.1%
Singh et al 411 1,035 3 0.29%

Rodriguez et al. Arch Int Med 1998; 158:33-39. McDonald et al. BMJ 1997; 315: 1333-1337.
Gutthann et al. Epidemiology 1997; 8 (1): 18-24. Singh G et al. Am J Med 1998; 105 (1B): 31S-38S.
Data on File: Searle
Withdrawal Rates for Adverse Events
6 Month Study (-041)
Diclofenac SR 75mg BID
25
Celecoxib 200mg BID
% patients withdrawn

20

15
p=0.001
10

0
0 2 4 6 8 10 12 14 16 18 20 22 24
Weeks
Geis GS et al. Arthritis & Rheum 1998;41(9) Suppl:1699A.
Data on File: Searle (Study 041)
Celecoxib Allergic
Reactions
Placebo Celecoxib NSAID
(n= 1864) (N=4146) (n= 2098)

Rash 2.1 % 2.2 % 1.8 %

Pruritus 1.7 % 1.5 % 1.2 %

Urticaria 0.3 % 0.5 % 0.6 %

Skin Disorder 0.3 % 0.2 % 0.6 %

Searle: Data on file

 CELEBREX™ (celecoxib):
A COX-2 Specific Inhibitor
 Phase III trials show that the promise of
science and technology has been kept
 Potent anti-inflammatory/analgesic
effects
 COX-1 sparing at clinical doses
 Unlike conventional NSAIDs, treatment
with celecoxib is no longer a “double-
edged sword”

10/17/08
CORTICOSTEROIDS
 類風濕 性關 節炎  
藥 物的 選擇
全身性皮質類固醇
研究顯示，全身性皮質類固醇能減緩疾病的進展。
雖然只有服藥時才能出現這種效力，但就減輕關節
的損傷來說，長期來說這或許能帶來好處。
低劑量 皮質類 固醇 是用來：
‧ 等待緩解時，抑制疾病的進展；
‧ 儘量縮減疾病在短時間內的活動力，比如說在疾
病突然惡化時；
‧ 服藥時，控制多餘的症狀並改善關節的功能。
 類風濕 性關 節炎  
藥 物的 選擇
 DMARD
 如果 NSAID 仍舊無法控制住類風濕性關節炎患者
的病情，那麼他們就可以 接受疾病改變抗風濕藥
物   (DMARD) 的治療。這種藥物治療的目的，主
要是用來緩解病情，並達到對該疾病的最大控制。
大多數的  DMARD 均能減緩類風濕性關節炎的進
展，並預防關節出現額外的惡化情形。總而言之
， DMARD 的作用 緩慢， 得花 上一到 六個 月才
能發
揮效力 。
 類風濕 性關 節炎  
藥 物的 選擇
是否選擇 DMARD 會受下列因素影響：
‧ （病患）服用的方便性
‧ 追蹤檢查的需要
‧ 毒性風險
‧ 醫師對病患預後的判斷
‧ 效力顯現的時間（有些 DMARD 得花上六個
月才會發揮效用，但大多數的病患只花二到三
個月的時間就享受到它的好處了。）
‧ 醫師對病患是否遵守服藥原則的判斷
‧ 藥物治療與追蹤檢查的花費
Azathioprine
Imuran 50mg/tab; 50mg/amp
 Indications
 Use Adjunct with other agents in prevention
of rejection of solid organ transplants; also
used in severe active rheumatoid arthritis
unresponsive to other agents; other
autoimmune diseases (ITP, SLE, MS, Crohn's
disease)
 Pregnancy Risk Factor D
 Lactation Excretion in breast milk
unknown/not recommended
 Contraindications Hypersensitivity to
azathioprine or any component of the
 Warnings/Precautions
 Chronic immunosuppression increases
the risk of neoplasia;
 has mutagenic potential to both men
and women and with possible
hematologic toxicities;
 use with caution in patients with liver
disease, renal impairment; monitor
hematologic function closely
 Adverse Reactions
 Dose reduction or temporary withdrawal
allows reversal
>10%:
 CNS: Fever, chills

 GIl: Nausea, vomiting, anorexia, diarrhea

 Hema: Thrombocytopenia, leukopenia,

anemia
 Miscellaneous: Secondary infection

1% to 10%:
 Derma: Rash Hema: Pancytopenia Hepatic:
Hepatotoxicity
 Drug Interactions
 Increased toxicity: Allopurinol may
increase serum levels of azathioprine's
active metabolite (6-MP). Decrease
azathioprine dose to 1/3 to 1/4 of normal
dose.

 Ethanol/Nutrition/Herb Interactions
Herb/Nutraceutical: Avoid cat's claw,
echinacea (have immunostimulant
properties).
 Mechanism of Action
 Azathioprine is an imidazolyl
derivative of 6-mercaptopurine;
antagonizes purine metabolism and may
inhibit synthesis of DNA, RNA, and proteins;
may also interfere with cellular metabolism
and inhibit mitosis
 Pharmacodynamics/Kinetics
 Distribution: Crosses placenta
 Protein binding: ~30%
 Metabolism: Extensively by hepatic
xanthine oxidase to 6-mercaptopurine
(active)
 Half-life elimination: Parent drug: 12
minutes; 6-mercaptopurine: 0.7-3 hours;
End-stage renal disease: Slightly prolonged
 Excretion: Urine (primarily as metabolites)
 Usual Dosage-1
 I.V. dose is equivalent to oral dose
(dosing should be based on ideal body
weight):
 Children and Adults:
Solid organ transplantation: Oral, I.V.:
2-5 mg/kg/day to start, then 1-2
mg/kg/day maintenance
 Adults: Rheumatoid arthritis:
Oral: 1 mg/kg/day for 6-8 weeks;
increase by 0.5 mg/kg every 4 weeks
until response or up to 2.5 mg/kg/day
 Usual Dosage-2
 Dosing adjustment in renal impairment:
 Clcr 10-50 mL/minute: Administer 75% of
normal dose daily
 Clcr<10 mL/minute: Administer 50% of
normal dose daily
 Hemodialysis: Slightly dialyzable (5% to
20%)
 Administer dose posthemodialysis: CAPD
effects: Unknown; CAVH effects: Unknown
 precautions
 Monitoring Parameters CBC, platelet counts, total
bilirubin, alkaline phosphatase
 Dietary Considerations May be taken with food.
 Patient Information Take as prescribed (may take in
divided doses or with food if GI upset occurs).
Rheumatoid arthritis: Response may not occur for up to
3 months; do not discontinue without consulting
prescriber.
 Organ transplant: Azathioprine will usually be
prescribed with other antirejection medications.
 Do not get pregnant while taking this medication;
use appropriate contraceptive measures. Breast-
feeding is not recommended.
 Cyclophosphamide
Endoxan 50mg/tab; 200mg/vial
 Indications
 Nononcologic: Prophylaxis of rejection for
kidney, heart, liver, and bone marrow
transplants, severe rheumatoid
disorders, nephrotic syndrome, Wegener's
granulomatosis, idiopathic pulmonary
hemosideroses, myasthenia gravis, multiple
sclerosis, systemic lupus erythematosus,
lupus nephritis, autoimmune hemolytic
anemia, idiopathic thrombocytic purpura
(ITP), macroglobulinemia, and antibody-
induced pure red cell aplasia
 Pregnancy Risk Factor D
 Precautions Dosage adjustment needed for
renal or hepatic failure; use with caution in
patients with bone marrow suppression.
 Cyclophosphamide preparation should be
performed in a Class II laminar flow biologic
safety cabinet. Personnel should be
wearing surgical gloves and a closed front
surgical gown with knit cuffs. Appropriate
safety equipment is recommended for
preparation, administration, and disposal of
antineoplastics.
 If cyclophosphamide contacts the skin,
wash and flush thoroughly with water.
Adverse Reactions-1
>10%:
 Dermatologic: Alopecia (40% to 60%) but
hair will usually regrow . Hair loss usually
begins 3-6 weeks after the start of
therapy.
 Endocrine & metabolic: Fertility: May
cause sterility; interferes with oogenesis
and spermatogenesis; may be irreversible
in some patients; gonadal suppression
(amenorrhea)
 GI: Nausea and vomiting occur more
frequently with larger doses, usually
beginning 6-10 hours after administration;
anorexia, diarrhea, mucositis, and
 Adverse Reactions-2
 GU: Severe, potentially fatal acute
hemorrhagic cystitis or urinary fibrosis,
believed to be a result of chemical irritation
of the bladder by acrolein, a
cyclophosphamide metabolite, occurs in
7% to 12% of patients and has been
reported in up to 40% of patients in
some series. Patients should be
encouraged to drink plenty of fluids (3-4
L/day) during therapy, void frequently, and
avoid taking the drug at night. With large
I.V. doses, I.V. hydration is usually
recommended. The use of mesna and/or
 Adverse Reactions-3
 Hematologic: Thrombocytopenia and
anemia are less common than
leukopenia
 Onset: 7 days
 Nadir: 10-14 days
 Recovery: 21 days
 Overdosage/Toxicology
 Overdosage/Toxicology Symptoms
of overdose include
myelosuppression, alopecia,
nausea, and vomiting. Treatment
is supportive.
 Drug Interactions-1
CYP2B6, 2D6, and 3A3/4 enzyme
substrate
 Decreased effect:

Digoxin: Cyclophosphamide may decrease

digoxin serum levels
 Increased toxicity:
Allopurinol may cause increase in bone
marrow depression and may result in
significant elevations of cyclophosphamide
cytotoxic metabolites
 Drug Interactions-2
 Increased toxicity:
2. Anesthetic agents: Cyclophosphamide
reduces serum pseudocholinesterase
concentrations and may prolong the
neuromuscular blocking activity of
succinylcholine; use with caution with
halothane, nitrous oxide, and
succinylcholine
3. Chloramphenicol results in prolonged
cyclophosphamide half-life to increase
toxicity
4. Cimetidine inhibits hepatic metabolism of
drugs and may decrease or increase the
 Drug Interactions-3
 Increased toxicity:
2. Doxorubicin: Cyclophosphamide may
enhance cardiac toxicity of anthracyclines
3. Phenobarbital and phenytoin induce
hepatic enzymes and cause a more rapid
production of cyclophosphamide
metabolites with a concurrent decrease in
the serum half-life of the parent compound
4. Thiazide diuretics: Leukopenia may be
prolonged
 Mechanism of Action
 Cyclophosphamide is an alkylating
agent that prevents cell division by
cross-linking DNA strands and
decreasing DNA synthesis. It is a cell
cycle phase nonspecific agent.
Cyclophosphamide also possesses
potent immunosuppressive activity.
Cyclophosphamide is a prodrug that
must be metabolized to active
metabolites in the liver.
 Pharmacodynamics/Kinetics
 Absorption: Oral: Well absorbed
 Distribution: Well; Vd: 0.48-0.71 L/kg; crosses
placenta; crosses into CSF (not high enough to
treat meningeal leukemia)
 Protein binding: 10% to 56%
 Metabolism: Hepatic into its active components:
acrolein, 4-aldophosphamide, 4-hydroperoxy-
cyclophosphamide, and nor-nitrogen mustard
 Bioavailability: >75%; Half-life elimination: 4-8
hours
 Time to peak, serum: Oral: ~1 hour
 Excretion: Urine (<30% as unchanged drug,
85% to 90% as metabolites)
 Usual Dosage
Children:
 SLE: I.V.: 500-750 mg/m2 every month;

maximum dose: 1 g/m2

 JRA/vasculitis: I.V.: 10 mg/kg every 2

weeks
Children and Adults:
 Oral: 50-100 mg/m2/day as continuous

therapy or 400-1000 mg/m2 in divided

doses over 4-5 days as intermittent
therapy
 Usual Dosage
Children and Adults: I.V.:
 Single Doses: 400-1800 mg/m2 (30-50 mg/kg)
per treatment course (1-5 days) which can be
repeated at 2-4 week intervals
 MAXIMUM SINGLE DOSE WITHOUT BMT is
7 g/m2(190 mg/kg) SINGLE AGENT
THERAPY
 Continuous daily doses: 60-120 mg/m2 (1-2.5
mg/kg) per day
 Autologous BMT: IVPB: 50 mg/kg/dose x 4 days
or 60 mg/kg/dose for 2 days; total dose is
usually divided over 2-4 days
 Nephrotic syndrome: Oral: 2-3 mg/kg/day every
day for up to 12 weeks when corticosteroids
are unsuccessful
 Methotrexate
MTX 2.5mg/tab; 50mg/2ml; 20mg, 1gm/vial
INDICATIONS
 Use Treatment of trophoblastic
neoplasms; leukemias; psoriasis;
rheumatoid arthritis (RA), including
polyarticular-course juvenile
rheumatoid arthritis (JRA); breast,
head and neck, and lung
carcinomas; osteosarcoma;
sarcomas; carcinoma of gastric,
esophagus, testes; lymphomas
 Pregnancy Risk Factor D

 Lactation Enters breast

milk/contraindicated
 Contraindications
 Contraindications Hypersensitivity
to methotrexate or any component
of the formulation; severe renal or
hepatic impairment; pre-existing
profound bone marrow suppression
in patients with psoriasis or
rheumatoid arthritis, alcoholic liver
disease, AIDS, pre-existing blood
dyscrasias; pregnancy
Warnings/Precautions
 May cause photosensitivity type reaction
 Reduce dosage in patients with renal or
hepatic impairment, ascites, and pleural
effusion.
 Use with caution in patients with peptic
ulcer disease, ulcerative colitis, or pre-
existing bone marrow suppression.
 Monitor closely for pulmonary disease;
use with caution in the elderly..
Warnings/Precautions
 Methotrexate given concomitantly
with radiotherapy may increase the
risk of soft tissue necrosis and
osteonecrosis.
 Safety and efficacy in pediatric
patients have been established only
in cancer chemotherapy and
polyarticular-course JRA.
 Warnings/Precautions
 Because of the possibility of severe toxic
reactions, fully inform patient of the risks
involved.
 May cause hepatotoxicity, fibrosis and
cirrhosis, along with marked bone marrow
depression.
 Death from intestinal perforation may
occur.
 Use caution when used with other
hepatotoxic agents (azathioprine,
 Warnings/Precautions
 Toxicity from methotrexate or any
immunosuppressive is increased in the
elderly.Must monitor carefully.
 For rheumatoid arthritis and
psoriasis, immunosuppressive therapy
should only be used when disease is
active and less toxic; traditional
therapy is ineffective.
 Recommended doses should be reduced
when initiating therapy in the elderly due
to possible decreased metabolism, reduced
renal function, and presence of interacting
 Overdosage/Toxicology
 Hydration and alkalinization may be used
to prevent precipitation of MTX or MTX
metabolites in the renal tubules.
 Generally, neither peritoneal nor
hemodialysis have been shown to increase
elimination.
 However, effective clearance of
methotrexate has been reported with
acute, intermittent hemodialysis using a
high-flux dialyzer.
 Leucovorin should be administered
intravenously, never intrathecally, for
overdoses of intrathecal methotrexate.
 Drug Interactions -1
Decreased effect:
 Corticosteroids: Reported to

decrease uptake of MTX into

leukemia cells. Administration of
these drugs should be separated
by 12 hours. Dexamethasone has
been reported to not affect
methotrexate influx into cells.
 Decreases phenytoin, 5-FU activity
 Drug Interactions-2
Increased toxicity:
 Live virus vaccines vaccinia
infections
 Vincristine: Inhibits MTX efflux
from the cell, leading to increased
and prolonged MTX levels in the
cell; the dose of VCR needed to
produce this effect is not achieved
clinically
 Drug Interactions-3
Increased toxicity:
 Vincristine: Inhibits MTX efflux from the

cell, leading to increased and prolonged

MTX levels in the cell; the dose of VCR
needed to produce this effect is not
achieved clinically
 Organic acids: Salicylates,

sulfonamides, probenecid, and high

doses of penicillins compete with MTX
for transport and reduce renal tubular
secretion. Salicylates and sulfonamides
may also displace MTX from plasma
 Drug Interactions-4
Increased toxicity:
 Ara-C: Increases formation of the

Ara-C nucleotide can occur when

MTX precedes Ara-C, thus
promoting the action of Ara-C
 Cyclosporine: CSA and MTX

interfere with each others renal

elimination, which may result in
increased toxicity
 Drug Interactions-5
Increased toxicity:
 NSAIDs: Should not be used during moderate

or high-dose methotrexate due to increased

and prolonged methotrexate levels (may
increase toxicity); NSAID use during
treatment of rheumatoid arthritis has not
been fully explored, but continuation of prior
regimen has been allowed in some
circumstances, with cautious monitoring
 Hepatotoxic agents (azathioprine, retinoids,

sulfasalazine) may increase the risk of

hepatotoxic reactions
 Ethanol/Nutrition/Herb Interaction
 Ethanol: Avoid ethanol (may be
associated with increased liver
injury).
 Food: Methotrexate peak serum
levels may be decreased if taken
with food. Milk-rich foods may
decrease MTX absorption. Folate
may decrease drug response.
 Herb/Nutraceutical: Avoid echinacea
(has immunostimulant properties).
 Mechanism of Action -1
 An antimetabolite that inhibits DNA
synthesis and cell reproduction in
malignant cells
 Cytotoxicity is determined by both drug
concentration and duration of cell
exposure; extracellular drug
concentrations of 1 x 10-8 M are required to
inhibit thymidylate synthesis; reduced
folates are able to rescue cells and reverse
MTX toxicity if given within 40 hours of the
MTX dose
 Mechanism of Action-2
 Folates must be in the reduced form (FH4) to
be active
 Folates are activated by dihydrofolate
reductase (DHFR)
 DHFR is inhibited by MTX (by binding
irreversibly), causing an increase in the
intracellular dihydrofolate pool (the inactive
cofactor) and inhibition of both purine and
thymidylate synthesis (TS)
 Pharmacodynamics/Kinetics-1
 Onset of action: Antirheumatic:
3-6 weeks; additional
improvement may continue
longer than 12 weeks
 Absorption: Oral: Rapid; well
absorbed at low doses (<30
mg/m2), incomplete after large
doses; I.M. injection: Complete
Pharmacodynamics/Kinetics-2
 Distribution: Penetrates slowly into 3rd
space fluids (eg, pleural effusions,
ascites), exits slowly from these
compartments (slower than from plasma);
crosses placenta; small amounts enter
breast milk; does not achieve therapeutic
concentrations in CSF; must be given
intrathecally if given for CNS prophylaxis
or treatment; sustained concentrations
retained in kidney and liver
 Protein binding: 50%
 Pharmacodynamics/Kinetics-3
 Metabolism: <10%; degraded by intestinal flora
to DAMPA by carboxypeptidase; hepatic
aldehyde oxidase converts MTX to 7-OH MTX;
polyglutamates are produced intracellularly and
are just as potent as MTX; their production is
dose and duration dependent and are slowly
eliminated by the cell
 Half-life elimination: Low dose: 3-10 hours; High
dose: 8-12 hours
 Time to peak, serum: Oral: 1-2 hours; Parenteral:
30-60 minutes
 Excretion: Primarily urine (44% to 100%);
 Usual Dosage(Children)-1
 Dermatomyositis: Oral: 15-20 mg/m2/week as a
single dose once weekly or 0.3-1 mg/kg/dose once
weekly
 Juvenile rheumatoid arthritis: Oral, I.M.:
Recommended starting dose: 10 mg/m2 once
weekly (at higher doses, gastrointestinal side
effects may be decreased with I.M.
administration); 5-15 mg/m2/week as a single dose
or as 3 divided doses given 12 hours apart
 Usual Dosage(Adults)-1

 Rheumatoid arthritis: Oral: 7.5 mg once

weekly OR 2.5 mg every 12 hours for 3
doses/week;
not to exceed 20 mg/week
 Bone marrow suppression is increased at
dosages >20 mg/week; absorption and
GI effects may be improved with I.M.
administration at higher end of dosage
range
 Usual Dosage(Adults)-2
 Psoriasis: Oral: 2.5-5 mg/dose every
12 hours for 3 doses given weekly or
Oral, I.M.: 10-25 mg/dose given once
weekly

 Ectopic pregnancy: I.M./I.V.: 50

mg/m2 single-dose without leucovorin
rescue
 Usual Dosage(Elderly)

Rheumatoid arthritis/psoriasis:
Oral: Initial: 5 mg once weekly; if
nausea occurs, split dose to 2.5 mg
every 12 hours for the day of
administration; dose may be
increased to 7.5 mg/week based on
response, not to exceed 20 mg/week
 Dosing adjustment in renal
impairment
 Clcr 61-80 mL/minute: Reduce dose
to 75% of usual dose
 Clcr 51-60 mL/minute: Reduce dose
to 70% of usual dose
 Clcr 10-50 mL/minute: Reduce dose
to 30% to 50% of usual dose
 Clcr<10 mL/minute: Avoid use
 HD & PD
 Hemodialysis: Not dialyzable (0%
to 5%); supplemental dose is not
necessary

 Peritoneal dialysis: Supplemental

dose is not necessary
Dosage adjustment in hepatic
impairment:
 Bilirubin 3.1-5 mg/dL or
AST >180 units: Administer 75% of
usual dose

 Bilirubin >5 mg/dL: Do not use

 Methotrexate Dosing Schedules

Dose Route Frequency

Conventional
P.O.
15-20 mg/m 2
Twice weekly
P.O., I.V.
30-50 mg/m 2
Weekly
15 mg/day for 5 days P.O., I.M. Every 2-3 weeks
Intermediate
I.V. push
50-150 mg/m 2
Every 2-3 weeks
240 mg/m * 2
I.V. infusion Every 4-7 days
0.5-1 g/m * 2
I.V. infusion Every 2-3 weeks
High
1-12 g/m *
2
I.V. infusion Every 1-3 weeks
*Followed with leucovorin rescue - refer to Leucovorin
monograph for details.
 Administration
 Specific dosing schemes vary, but high
dose should be followed by leucovorin
calcium 24-36 hours after initiation of
therapy to prevent toxicity
 Renal toxicity can be
minimized/prevented by alkalinizing the
urine (with sodium bicarbonate) and
increasing urine flow (hydration
therapy)
 Monitoring Parameters
 Monitoring Parameters For prolonged
use (especially rheumatoid arthritis,
psoriasis) a baseline liver biopsy,
repeated at each 1-1.5 g cumulative
dose interval, should be performed;
WBC and platelet counts every 4
weeks; CBC and creatinine, LFTs
every 3-4 months; chest x-ray
 Patient Information-1
 Avoid alcohol to prevent serious side effects.
 Avoid intake of extra dietary folic acid,
maintain adequate hydration (2-3 L/day of
fluids unless instructed to restrict fluid
intake) and adequate nutrition (frequent
small meals may help).
 You may experience nausea and vomiting
(small frequent meals may help or request
antiemetic from prescriber); drowsiness,
tingling, numbness, or blurred vision (avoid
driving or engaging in tasks that require
alertness until response to drug is known);
 Patient Information-2
 Mouth sores (frequent oral care is
necessary);
 loss of hair; permanent sterility; skin rash;
photosensitivity (use sunscreen, wear
protective clothing and eyewear, and avoid
direct sunlight).
 Report black or tarry stools, fever, chills,
unusual bleeding or bruising, shortness of
breath or difficulty breathing, yellowing of
skin or eyes, dark or bloody urine, or acute
 Pregnancy/breast-feeding
precautions

 Do not get pregnant while taking

this medication; use appropriate
barrier contraceptive measures.
The drug may cause permanent
sterility and may cause birth
defects.
 Do not breast-feed.
Sulfasalazine
Salicylazosulfapyridine
Dosage Forms Tablet: 500 mg
Tablet, enteric coated: 500 mg
 USE
Use Management of ulcerative colitis; enteric
coated tablets are also used for rheumatoid
arthritis (including juvenile rheumatoid arthritis) in
patients who inadequately respond to analgesics and
NSAIDs
Use - Unlabeled/Investigational Ankylosing
spondylitis, collagenous colitis, Crohn's
disease, psoriasis, psoriatic arthritis,
juvenile chronic arthritis
Pregnancy Risk Factor B/D (at term)
 Pregnancy & Lactation
 Pregnancy Implications Sulfonamides are
excreted in human breast milk and may
cause kernicterus in the newborn. Although
sulfapyridine has poor bilirubin-displacing
ability, use with caution in women who are
breast-feeding.
Lactation Enters breast milk/use caution (AAP
recommends use "with caution")
Contraindications Hypersensitivity to
sulfasalazine, sulfa drugs, salicylates, or any
component of the formulation; porphyria; GI
or GU obstruction; children <2 years of age;
 Warnings/Precautions
Use with caution in patients with renal
impairment; impaired hepatic function or
urinary obstruction, blood dyscrasias, severe
allergies or asthma, or G6PD deficiency; may
cause folate deficiency (consider providing 1
mg/day folate supplement). Chemical
similarities are present among sulfonamides,
sulfonylureas, carbonic anhydrase inhibitors,
thiazides, and loop diuretics (except
ethacrynic acid). Use in patients with
sulfonamide allergy is specifically
contraindicated in product labeling,
 Adverse Reactions
>10%:
 Central nervous system: Headache (33%)

 Dermatologic: Photosensitivity

 Gastrointestinal: Anorexia, nausea, vomiting,

diarrhea (33%), gastric distress

 Genitourinary: Reversible oligospermia

(33%)
<3%:
 Dermatologic: Urticaria/pruritus (<3%)

 Hematologic: Hemolytic anemia (<3%),

Heinz body anemia (<3%)

 Mechanism of Action
Acts locally in the colon to
decrease the inflammatory
response and systemically
interferes with secretion by
inhibiting prostaglandin
synthesis
 Drug Interactions-1
Azathioprine, mercaptopurine, sulfasalazine:
May increase the risk of myelosuppression
(due to TPMT inhibition).
Cyclosporine concentrations may be decreased;
monitor levels and renal function

Digoxin's absorption may be decreased

Folic acid's absorption may be decreased

Hypoglycemics: Increased effect of oral

hypoglycemics (rare, but severe); monitor
blood sugar
 Drug Interactions-2
Methotrexate-induced bone marrow
suppression may be increased
NSAIDs and salicylates: May increase
sulfonamide concentrations
Thiazide diuretics: May increase the
incidence of thrombocytopenia purpura
Warfarin and other oral anticoagulants:
Anticoagulant effect may be increased;
decrease dose and monitor INR closely
 Pharmacodynamics/Kinetics
 Absorption: 10% to 15% as unchanged drug from
small intestine
 Distribution: Small amounts enter feces and breast
milk
 Metabolism: Via colonic intestinal flora to
sulfapyridine and 5-aminosalicylic acid (5-ASA); following
absorption, sulfapyridine undergoes N-acetylation and
ring hydroxylation while 5-ASA undergoes N-acetylation
 Half-life elimination: 5.7-10 hours
 Excretion: Primarily urine (as unchanged
drug, components, and acetylated
metabolites)
 Dosage Oral-1
 Children 6 years:
Juvenile rheumatoid arthritis:
30-50 mg/kg/day in 2 divided
doses; Initial: Begin with 1/4 to
1/3 of expected maintenance
dose; increase weekly;
maximum: 2 g/day typically
 Dosage Oral-2
 Adults: Enteric coated tablet:
 Ulcerative colitis: Initial: 1 g 3-4
times/day, 2 g/day maintenance in
divided doses; may initiate therapy with
0.5-1 g/day
 Rheumatoid arthritis: Initial: 0.5-1
g/day; increase weekly to maintenance
dose of 2 g/day in 2 divided doses;
maximum: 3 g/day (if response to 2 g/day
is inadequate after 12 weeks of
Dosing interval in renal impairment

 Clcr 10-30 mL/minute: Administer

twice daily
 Clcr<10 mL/minute: Administer
once daily
 Dosing adjustment in hepatic
impairment: Avoid use
 Administration
GI intolerance is common during the
first few days of therapy (administer
with meals).
Dietary Considerations Since
sulfasalazine impairs folate
absorption, consider providing 1
mg/day folate supplement.
 Patient Information-1
 Do not crush, chew, or dissolve coated
tablets.
 Do not take on an empty stomach or with
antacids.
 Maintain adequate hydration (2-3 L/day of
fluids unless instructed to restrict fluid
intake) to prevent kidney damage.
 Increased dietary iron may be
recommended. You may experience
nervousness or dizziness (use caution when
driving or engaging in hazardous activities
 Patient Information-2
 You may experience photosensitivity (use
sunscreen, wear protective clothing and
eyewear, and avoid direct sunlight).
Orange-yellow color of urine, sweat, tears is
normal and will stain contact lenses and
clothing. Report rash, persistent nausea or
anorexia, or lack of improvement in
symptoms (after 1-2 months).
Pregnancy/breast-feeding precautions:
Inform prescriber
Hydroxychloroquine

Dosage Forms Tablet, as

sulfate: 200 mg [base 155 mg]
Plaquenil®
 USE
 Use Suppression and treatment of acute
attacks of malaria; treatment of systemic
lupus erythematosus and rheumatoid
arthritis
Use - Unlabeled/Investigational Porphyria
cutanea tarda, polymorphous light eruptions
Pregnancy Risk Factor C
Lactation Enters breast milk/compatible
Contraindications Hypersensitivity to
hydroxychloroquine, 4-aminoquinoline
derivatives, or any component of the
formulation; retinal or visual field changes
 Warnings/Precautions
Use with caution in patients with
hepatic disease, G6PD deficiency,
psoriasis, and porphyria; long-term
use in children is not recommended;
perform baseline and periodic (6
months) ophthalmologic
examinations; test periodically for
muscle weakness
 Adverse Reactions-1
CNS: Irritability, nervousness, emotional changes,
nightmares, psychosis, headache, dizziness,
vertigo, seizures, ataxia, lassitude
Derm: Bleaching of hair, alopecia, pigmentation
changes (skin and mucosal; black-blue color),
rash
Endocrine and metabolic: Weight loss
GI: Anorexia, nausea, vomiting, diarrhea,
cramping
Hematologic: Aplastic anemia, agranulocytosis,
leukopenia, thrombocytopenia, hemolysis (in
patients with glucose-6-phosphate deficiency)
 Adverse Reactions-2
 Ocular: Disturbance in accommodation,
keratopathy, corneal changes/deposits
(visual disturbances, blurred vision,
photophobia - reversible on discontinuation),
macular edema, atrophy, abnormal
pigmentation, retinopathy (early changes
reversible - may progress despite
discontinuation if advanced), optic disc
pallor/atrophy, attenuation of retinal
arterioles, pigmentary retinopathy,
scotoma, decreased visual acuity, nystagmus
 Otic: Tinnitus, deafness
 Overdosage/Toxicology
Symptoms of overdose include
headache, drowsiness, visual
changes, cardiovascular collapse,
and seizures followed by
respiratory and cardiac arrest.
Treatment is symptomatic. Urinary
alkalinization will enhance renal
elimination.
 Drug Interactions
 Chloroquine and other 4-
aminoquinolones may be decreased due
to GI binding with kaolin or magnesium
trisilicate
 Increased effect: Cimetidine increases
levels of chloroquine and probably other
4-aminoquinolones
 Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (due to GI
irritation).
 Mechanism of Action
Interferes with digestive vacuole
function within sensitive malarial
parasites by increasing the pH and
interfering with lysosomal
degradation of hemoglobin; inhibits
locomotion of neutrophils and
chemotaxis of eosinophils; impairs
complement-dependent antigen-
antibody reactions
 Pharmacodynamics/Kinetics
 Onset of action: Rheumatic disease: May require
4-6 weeks to respond
 Absorption: Complete
 Protein binding: 55%
 Metabolism: Hepatic
 Half-life elimination: 32-50 days
 Time to peak: Rheumatic disease: Several
months
 Excretion: Urine (as metabolites and
unchanged drug); may be enhanced by
urinary acidification
 DOSE
 Dosage Note: Hydroxychloroquine
sulfate 200 mg is equivalent to 155
mg hydroxychloroquine base and
250 mg chloroquine phosphate.
Oral: Children:
JRA or SLE: 3-5 mg/kg/day divided 1-2
times/day;
avoid exceeding 7 mg/kg/day
 DOSE-2
Adults:
 Rheumatoid arthritis: 310-465 mg/day to
start taken with food or milk; increase dose
until optimum response level is reached;
usually after 4-12 weeks dose should be
reduced by 1/2 and a maintenance dose of
155-310 mg/day given
 Lupus erythematosus: 310 mg every day or
twice daily for several weeks depending on
response; 155-310 mg/day for prolonged
maintenance therapy
 PRECAUTIONS
 Administration Administer with food or
milk
Monitoring Parameters Ophthalmologic
exam, CBC
Dietary Considerations May be taken
with food or milk.
 Patient Information-1
 It is important to complete full course of
therapy which may take up to 6
months for full effect.
 May be taken with meals to decrease GI
upset and bitter aftertaste. Avoid
alcohol.
 You should have regular ophthalmic
exams (every 4-6 months) if using this
medication over extended periods.
 Patient Information-2
 You may experience dizziness, headache,
nervousness, or lightheadedness (use
caution when driving or engaging in tasks
requiring alertness until response to drug is
known);
 Increased sensitivity to sunlight
 Report vision changes, rash or itching,
persistent diarrhea or GI disturbances,
change in hearing acuity or ringing in the
ears, chest pain or palpitation, CNS
changes, unusual fatigue, easy bruising or
bleeding, or any other persistent adverse
 Penicillamine

Dosage Forms Capsule: 125 mg, 250 mg

Tablet: 250 mg
 USE
 Use Treatment of Wilson's disease,
cystinuria, adjunct in the treatment of
rheumatoid arthritis; lead, mercury,
copper, and possibly gold poisoning. (Note:
Oral DMSA is preferable for lead or mercury
poisoning); primary biliary cirrhosis; as
adjunctive therapy following initial
treatment with calcium EDTA or BAL
Pregnancy Risk Factor D
Lactation Enters breast milk/contraindicated
 Contraindications
Hypersensitivity to penicillamine or any
component of the formulation; renal
insufficiency; patients with previous
penicillamine-related aplastic anemia or
agranulocytosis; concomitant
administration with other
hematopoietic-depressant drugs
(eg, gold, immunosuppressants,
antimalarials, phenylbutazone);
pregnancy
 Warnings/Precautions
 Cross-sensitivity with penicillin is
possible; therefore, should be used
cautiously in patients with a history of
penicillin allergy.
 patients should be warned to report
promptly any symptoms suggesting
toxicity; approximately 33% of
patients will experience an allergic
reaction; since toxicity may be dose
related, it is recommended not to
exceed 750 mg/day in elderly.
 Adverse Reactions-1
>10%:
 Dermatologic: Rash, urticaria, itching (44% to

50%)
 GI: Hypogeusia (25% to 33%)

 Neuromuscular & skeletal: Arthralgia

1% to 10%:
 CV: Edema of the face, feet, or lower legs

 CNS: nervous system: Fever, chills

 GI: Weight gain, sore throat GU: Bloody or cloudy

urine
 Hema: Aplastic or hemolytic anemia,
 Drug Interactions
 Decreased effect with iron and zinc salts,
antacids (magnesium, calcium, aluminum) &
food
 Decreased effect/levels of digoxin
 Increased effect of gold, antimalarials,
immunosuppressants, phenylbutazone
(hematologic, renal toxicity)
 Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid or limit ethanol.
Food: Penicillamine serum levels may be
decreased if taken with food. Do not
 Mechanism of Action
 Chelates with lead, copper, mercury
and other heavy metals to form
stable, soluble complexes that are
excreted in urine; depresses
circulating IgM rheumatoid factor,
depresses T-cell but not B-cell activity;
combines with cystine to form a
compound which is more soluble, thus
cystine calculi are prevented
 Pharmacodynamics/Kinetics
 Absorption: 40% to 70%
 Metabolism: Hepatic, small amounts
 Protein binding: 80% to albumin
 Half-life elimination: 1.7-3.2 hours
 Time to peak, serum: ~2 hours
 Excretion: Primarily urine (30% to
60% as unchanged drug)
 DOSE
 Dosage Oral: Rheumatoid arthritis:
 Children: Initial: 3 mg/kg/day ( 250 mg/day)
for 3 months, then 6 mg/kg/day ( 500
mg/day) in divided doses twice daily for 3
months to a maximum of 10 mg/kg/day in
3-4 divided doses
 Adults: 125-250 mg/day, may increase
dose at 1- to 3-month intervals up to 1-1.5
g/day
 ADMINISTRATION
 Dosing adjustment/comments in
renal impairment: Clcr<50
mL/minute: Avoid use
 Administration Administer on an
empty stomach (1 hour before meals
and at bedtime). Patients unable to
swallow capsules may mix contents
of capsule with fruit juice or chilled
pureed fruit.
 Monitoring Parameters
 Urinalysis, CBC with differential, platelet
count, liver function tests; weekly
measurements of urinary and blood
concentration of the intoxicating metal is
indicated (3 months has been tolerated)
 CBC: WBC <3500/mm3, neutrophils
<2000/mm3 or monocytes >500/mm3
indicate need to stop therapy immediately;
quantitative 24-hour urine protein at 1- to 2-
week intervals initially (first 2-3 months);
urinalysis, LFTs occasionally; platelet counts
<100,000/mm3 indicate need to stop
 Dietary Considerations
 Dietary Considerations Should be taken at
least 1 hour before a meal on an empty
stomach. Iron and zinc may decrease drug
action; increase dietary intake of
pyridoxine. For Wilson's disease, decrease
copper in diet and omit chocolate, nuts,
shellfish, mushrooms, liver, raisins,
broccoli, and molasses.
For lead poisoning, decrease calcium in
diet.
 Patient Information-1
 Take this medication exactly as directed;; do not
take with milk or milk products. Avoid or limit
alcohol and excess intake of vitamin A.
 It is preferable to take penicillamine on empty
stomach (1 hour before or 2 hours after meals).
Maintain adequate hydration (2-3 L/day of fluids
unless instructed to restrict fluid intake).
 Wilson's disease: Avoid chocolate, shellfish, nuts,
mushrooms, liver, broccoli, molasses.
 Lead poisoning: Decrease dietary calcium.
 Patient Information-2
 Cystinuria: Take with large
amounts of water.
 Pregnancy/breast-feeding
precautions: Do not get pregnant
while taking this medication; use
appropriate contraceptives. Do not
breast-feed.
CyCLOSPORINE

Neoral cap 50mg; 100mg/cap

Solution 100mg/ml;50ml/bot
INJ 50mg/ml/amp
Pharmacology

● Selectively and reversibly inhibits

T-lymphocyte activation without
causing myelosuppression
● Blocks interleukin-2 (T-cell growth
factor) production
 Cyclosporine
Cyclosporin A, Sandimmune, CsA, CyA

● History
Approved by FDA in 1983
● Chemistry
- Fungal metabolite
- Cyclic Polypeptide (11 amino acids) with
a high MW
- Neutral and hydrophobic (nonpolar) product
 Pharmacokinetics
● Absorption :
slow, variable and incomplete (30%),
peak conc. at 2-4 hrs
↑ abs. with time, ↓ abs. from T-tube
● Distribution :
widely distributed throughout the body
primarily in liver, pancreas, and lung highly
protein bound (mainly RBC) not dialyzed
Pharmacokinetics
● Metabolism :
extensively metabolized by the liver
(cytochrome p-450 enzyme)
● Elimination :
primarily excreted via biliary
 Dosage & Administration
● Oral --- 5 ～ 18 mg/kg/day initially in 1-2
doses, mix with chocolate milk or fruit juice in a
glass container
● I.V. --- 2 ～ 6 mg/kg/day over 2-6 hrs infusion
IV dose = 1/3 oral dose
dilute 50mg CsA in 20-100ml 0.9% NaCl or 5%
D/W
use glass container only
use NTG IV set
 Parameters to Monitor

● CsA trough level --- 100 ～ 200 ng/ml

(whole blood, TDx)
● Renal function --- I/O, BUN / Cr
● Hepatic Function --- LFTs, Bilirubin
 Use
Prophylaxis of organ rejection in kidney,
liver, and heart transplants, has been
used with azathioprine and/or
corticosteroids; severe, active rheumatoid
arthritis (RA) not responsive to
methotrexate alone; severe, recalcitrant
plaque psoriasis in nonimmunocompromised
adults unresponsive to or unable to tolerate
other systemic therapy
 Use
Unlabeled/Investigational Short-term, high-
dose cyclosporine as a modulator of
multidrug resistance in cancer treatment;
allogenic bone marrow transplants for
prevention and treatment of graft-versus-
host disease; also used in some cases of
severe autoimmune disease (ie, SLE,
myasthenia gravis) that are resistant to
corticosteroids and other therapy; focal
segmental glomerulosclerosis

Pregnancy Risk Factor C

 Contraindications
Hypersensitivity to cyclosporine or any
component of the formulation.
Rheumatoid arthritis and psoriasis:
Abnormal renal function, uncontrolled
hypertension, malignancies. Concomitant
treatment with PUVA or UVB therapy,
methotrexate, other immunosuppressive
agents, coal tar, or radiation therapy are
also contraindications for use in patients
with psoriasis.
 Warnings/Precautions
 Dose-related risk of nephrotoxicity and
hepatotoxicity; monitor renal function and
adjust dose appropriately.
 Use caution with other potentially
nephrotoxic drugs (eg, acyclovir,
aminoglycoside antibiotics, amphotericin
B, ciprofloxacin).
 Increased risk of lymphomas, other
malignancies, infection. May cause
hypertension.
Warnings/Precautions
 Psoriasis: Patients should avoid
excessive sun exposure; safety and
efficacy in children <18 have not
been established
 Rheumatoid arthritis: Safety and
efficacy for use in juvenile
rheumatoid arthritis have not been
established
 Side Effects
● Nephrotoxicity # ● Infection
● Hypertention * # (bacteria, viral, fungal)
● Neurologic changes* ● Hepatoxicity*
(tremor, numbness) ● Convulsions
● Hirsutism*
● Thrombocytopenia &
● Gum hyperplasia*
hemolytic anemia
● Electrolyte disturbance
(↑K,↓Mg,↑uric acid )
● Lymphoma*
Note: * dose-dependent
# difficult to differentiate CsA toxicity from renal rejection)
Efficacy Comparison
 ENBREL 恩博 (etanercept)
 Dimeric fusion protein
 Human p75, Soluble, extracellular domain of
tumor necrosis factor-α (TNFα) linked to Fc portion
of IgG1
 934 amino acid
 Molecular weight: 150 kD
 Recombinant DNA technology
 Produced by Chinese Hamster Ovary (CHO) cell
line
 Pharmacotherapeutic group: selective
immunosuppressant agent
 New Generation of Biotechnology
Agents-Biological Response Modifier
ENBREL Pharmacokinetics
Pharmacokinetics
C max :48 hours
Bioavailability :76%
Vd: 7.6 l
Half-life: 70 hours
Clearance: 0.066 l/hr
No difference between men and women
MTX has no effect on the pharmacokinetics of Enbrel
No increase concentration of Enbrel in renal and hepatic impairment
ENBREL Usage
Dose
Adult (18-64 y/o): 25mg, sc, twice weekly
Child (4-17): 0.4mg/kg, sc, twice weekly
No dose adjustment for elderly patients (≧65y/o), renal and hepatic
impairment
Notes
No special routine examination
Major adverse effects: inject site reaction
Stop ENBREL when Infection
ENBREL (etanercept) 恩博
ENBREL 的療效對病人的利益
 可恢復患者日常生活能力
 實現患者的願望
 保存患者關節的功能
ENBREL (etanercept) 恩博
ENBREL 的使用方式
 成人 :25mg 皮下注射 , 一星期二次
 小孩 :0.4mg/kg, 皮下注射 , 一星期二次
 不需特殊的實驗室檢查
 適應症 :
 類風濕性關節炎

 幼年型類風濕關節炎

 牛皮癬關節炎
ARHEUMA 雅努麻 ®

(Leflunomide)

Immuno-modulator
DMARD for Rheumatoid
Arthritis

LOTUS Pharm.Co.
Ltd.
ArheumaTM
20mg/Tab.
適應症 :
治療成人類風濕性關節炎，
並減緩於 X 光所顯現之關節磨
損與關節間隙狹窄等結構性損
害。
Outlines
 Mechanism of Arheuma
 Pharmacokinetics
 Contraindications
 Warning
 Precautions
 Drug Interactions
 Side Effects
 Dosage and Administration
Mechanism of Arheuma
 Inhibiting the amplification of T, B
cell
 Anti-inflammatory effects
 Reducing the production of PGE2
 Increasing the producing of IL-1
receptor antagonist in human
synovial fibroblasts and articular
chondrocytes
 Suppressing the activation of NFkB
 Pharmacokinetics I
Major active metabolite: A77 1726 (M1)
Absorption ：
 No food interaction

 BA ： 80%

 Peak level of M1 ： 6-12 hours after dosing

Distribution ：
 Low Vd ： (Vss=0.13 L/kg)

 Extensively bound (>99.3%) to albumin

 Linear pharmacokinetics

ARAVATM Prescribing Information US, 1998.

Pharmacokinetics II
 Metabolism ： M1
 Elimination
 Excretion of radiolabeled A77 1726:
approximately 43% in urine, 48% in feces
 Clearance ： 31 mL/hr
 T 1/2 ： 2 weeks (biliary recycling)
 Accelerate elimination with:
 cholestyramine
 activated charcoal
 Pharmacokinetics III
Special populations
 Smoking ： have a 38% increase in clearance

 Chronic Renal Insufficiency


M1 is not dialyzable (CAPD or hemodialysis)

Free fraction of M1 are almost doubled

Caution
 Hepatic Insufficiency ： is not recommended

 輕度腎臟功能不全之病患不需要調整劑量。

 65 歲以上之病患不需要調整劑量。

Weber & Harnisch 1998 Rheumatol Eur 27(Suppl 2):110.

Contraindication
 Hypersensitivity to leflunomide
or any other components of
Arheuma
 Women who are or may become
pregnant
 Warnings
 Immunosuppression potential/ Bone
marrow supression
 Hepatotoxicity
 Pre-existing hepatic disease
 Significant hepatic impairment or
evidence of infection with hepatitis B or C
 Skin reactions
 Malignancy
 Precautions
Need for Drug Elimination
Laboratory Tests :
 Hematologic Monitoring (WBC, Hb, platelet)

 Liver Enzyme Monitoring (AST,ALT,Serium

albumin)
 服藥前及用藥後的前六個月， 每隔四週測，之後每隔 6-

8 週監測
Pregnancy : X
Nursing Mothers (excreting to human milkunknown)
治療期間使用有效避孕方式 , 只要活性代謝物 M1 之血漿濃
度高於 0.02mg/l 不可懷孕
男性病患應注意：
 可能有男性引起的胎兒毒性，服藥期間應使用有效的避

孕方法。
Drug Interactions
 Warfarin did not affect M1 protein
binding
 M1 會取代 ibuprofen 、 diclofenac 與的
protein binding 。這些藥物游離態的部分
僅增加 13% 至 50% ，但不具有臨床意義
 M1 inhibits CYP 450 2C9, which is
responsible for the metabolism of
phenytoin, tobutamide, warfarin,
NSAIDs
 Rifampin ： M1 peak levels
increases(~40%)
 如何預防類風濕關節炎
 類風濕關節炎是一種以關節炎症為主的全
身性的疾病，好發的對象以女性多於男性、成人
多於兒童，雖然目前確實的病因不明，不過，預
防勝於治療，平常就應該具備預防類風濕關節炎
的概念。
 ( 一）常常運動、鍛鍊體魄：例如早上起床後
能做做體操、練氣功、打太極拳或散步；因為
有運動就能增強抵抗力，日常生活裏也就較不
易生病。
 如何預防類風濕關節炎
 （二）避免受到風寒、防止潮濕環境：盡可能
要受涼、淋雨或受潮，例如不要穿已濕的衣
服、鞋子或襪子，不要住太過潮濕的地方，不
要暴飲冰水等等。

 （三）避免過度疲勞：除了飲食有節之外，應
當盡量讓自己不要太過勞累，使身體產生疾病
，懂得適度的工作和休閒。
 如何預防類風濕關節炎
 ( 四 ) 保持心情的愉悅：有時候類風濕關節炎
的患者是因心理上或精神上受到刺激、過度悲
傷才罹患此症的，所以懂得調節自己的心情是
很重要的。

 ( 五 ) 預防和控制感染：在病歷上像患有扁桃腺炎
、鼻竇炎或是齲齒等感染後，也會有類風濕關節
炎，所以應預防受到一些疾病感染，並早期治癒。
treatment of rheumatoid at an early
stage
ACTIVE DISEASE
EARLY DISEASE
LATE DISEASE
GOOD PROGNOSIS POOR PROGNOSIS
GENERALISED LOCALISED
Pulse corticosteroid therapy
Synovectomy
Hydroxychloroquine Sulfasalazine Intra-articular
Age ＜ 65 Age ＞ 65
NO RESPONSE Joint surgeryj
PARTIAL RESPONSE
or TO THERAPY
LOSS OF EFFICACY Oral corticosteroid
Pulse corticosteroid therapy
(low dose)
Add other agents to Methotrexate or IM gold
Existing drug therapy
NO RESPONSE TO THERAPY
RESPONSE TO THERAPY
Cyclosporin
Maintenance therapy with IM gold Azathioprine
Exerimental therapies