20070512 臨床治療學 - Rheumtoid Arthritis (RA)

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至目前為止仍無法完全治癒。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 -Arthritis

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第二大無法就業原因估計每年對經濟影響有估計每年對經濟影響有 650650億美元億美元

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。另一路徑為，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±.

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.

DIAGNOSIS > Rheumatoid Arthritis

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。


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。


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

Education, counseling, physical therapy, changes in

lifestyle

Fast-acting non-steroidal anti-inflammatory drugs

Slow-acting anti-inflammatory drugs

Systemic corticosteroids

Cytotoxic therapy

ExperimentalSurgery Local corticosteroid

injections

Pyramidal schema of the treatment of RA

Sawtooth Paradigm

Strategies of combining antirheumatic drug

Time

Step-down bridge

Time

Time Time

Step-up

Overlap and Switch Parallet

NSAIDs

NSAID-Gastropathy: U.S. Mortality Data for Several Selected Disorders in 1997

20,197

16,685 16,500

10,503

5,3384,441

1,437

0

5,000

10,000

15,000

20,000

25,000

Cause of Death

No

. o

f D

ea

ths

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

=33

一般常用的 NSAIDS

商品名 Relifex Voltaren Naprosyn Brufen Cinopal Indocid Profenid Surgam Tilcotil Feldene Mobic

製造廠美占史克汽巴嘉基中化 Kaken 氰胺默克 Rhone-poulenc 龍壽 / 赫斯特羅氏 Pfizer 百靈佳

化學名稱 nabumetone diclofenac naproxen ibuprofen fenbufen indomethacin ketoprofen tiaprofenic acid tenoxicam piroxicam Meloxicam

Selective vs Specific

COX-1Selective

(Ratio > 1)

Equipotent forCOX-1 and COX-2

(Ratio = 1)

COX-2

Selective(Ratio < 1)

AspirinIndometha

cinSulindac

PiroxicamNaproxenDiclofenacIbuprofen

NabumetoneEtodolac

Meloxicam*Nimesulide

**

*Meloxicam Boerhinger-Ingelheim

**Nimesulide Various

COX-2

Specific(Ratio< < 1)

Celecoxib ~1/400

Rofecoxib (VIOXX)

~1/1000

BUTAZOLIDIN

Salicylic

Propionic AnthranilicAcetic

oxicamscarboxilic

acidspyrazolones

phenylacetic acid

efficacyWHY SO MANY ?

ASPIRIN 1898 Indoleacetic acid

non-acetyl

safety

Nabumetone

IbuprofenKetoprofenNaproxen

Tolmetin

Mefenamic acid

Diclofenac

PiroxicamMeloxicam

DOLOBIDSulindacEtodolac

TRILISATEDISALCID

pyrolacetic acidIndomethacin

NSAIDs

112/04/08

HypothesisCOX-2 Specific Inhibitors

will be anti-inflammatory and analgesic without thetypical side effects

of NSAIDs.

Prostaglandins and Renal

Function

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.

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 TherapyGoals of Arthritis Therapy Achieved by conventionalGoal 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

Achieved by conventionalGoal 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 CyclooxygenaseTwo Forms of Cyclooxygenase

Produces prostanoids that mediate homeostaticfunctions

Constitutively expressed

Especially important in:– Gastric mucosa; small

and large bowel mucosa– Kidney– Platelets– Vascular endothelium

Produces prostanoids that mediate homeostaticfunctions

Constitutively expressed

Especially important in:– Gastric mucosa; small

and large bowel mucosa– Kidney– Platelets– Vascular endothelium

Cyclooxygenase-1 (COX-1)Cyclooxygenase-1 (COX-1)

Produces prostanoids that mediate inflammation, pain, and fever

Induced mainly at sites of inflammation by cytokines

Constitutive expression in:– Brain– Kidney (mainly animal data)

Produces prostanoids that mediate inflammation, pain, and fever

Induced mainly at sites of inflammation by cytokines

Constitutive expression in:– Brain– Kidney (mainly animal data)

Cyclooxygenase-2 (COX-2)Cyclooxygenase-2 (COX-2)

DuBois et al. FASEB J. 1998; 12: 1063–1073DuBois et al. FASEB J. 1998; 12: 1063–1073

Diagrammatic Representations of the COX-1 and COX-2 Structure

As Determined by X-Ray Crystallography

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

COX-1 COX-2

Hydrophilic “side pocket”

Hydrophobicchannel

N-terminal N-terminal

Hydrophobicchannel

Bulky isoleucineat position523 closeshydrophilic“side pocket”

Smallervaline at

523 openshydrophilic

“side pocket””

Arginineat 120

C-terminalcontainingactive sites


Arginineat 120

COX / Substrate Interaction

COX-1

N-terminal

Arginineat 120


Arach

idon

ic Acid PG


Classical NSAID: Non-specific binding to COX-1 and COX-2

Terminal Carboxylic Acid Plays an Important RoleCOX-1

N-terminal

Carboxylicgroup

of NSAIDforms

“salt bridge”with

Arginineat 120


Arach

idonic Acid

NSAID(flurbiprofen)phenyl group

binds tohydrophobic

channel

COX-2

N-terminal

Carboxylicgroup

of NSAIDforms“salt

bridge”with

Arginineat 120


Arach

idonic Acid

NSAID(flurbiprofen)phenyl group

binds tohydrophobic

channel


Celecoxib: A “Purpose Designed” Specific COX-2

Inhibitor

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

Polar sulfonamidegroup to bind to hydrophilic “side pocket”

Methylphenyl group to bind tohydrophobic channel

No terminal acidgroup to bind to Arg120 in COX-1

3

NN

H C

CF3

S

NH2

OO

OO

Specific COX-2 Inhibitor Binding to COX-2

Exploitation of the “Side Pocket”

COX-2

Hydrophilic “side pocket”

N-terminal


Arg 513,Hist 90 – forms hydrogen bonds with oxygen in sulfonamide side chain

Specific COX-2 inhibitor – phenyl group binds tohydrophobic channel

Arach

idonic Acid

Arg 120

Kurumbail et al. Kurumbail et al. NatureNature 1996; 384: 644-648 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)

PharmacokineticsCelecoxib

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

CelecoxibCelecoxib

CFCF33

NNNN

SOSO2 2 NHNH22

P450 2C9P450 2C9

HydroxylationHydroxylation

CFCF33

NNNN

Glucuronide of theGlucuronide of theAcid MetaboliteAcid Metabolite

(urinary)(urinary)

SOSO2 2 NHNH22

Glucuronide-OOCGlucuronide-OOC

CFCF33

NNNN

SOSO2 2 NHNH22

Inactive AlcoholInactive AlcoholMetaboliteMetabolite

HOHHOH2 2 CC

CFCF33

NNNN

SOSO2 2 NHNH22

HOOCHOOC

OxidationOxidation

Inactive AcidInactive AcidMetabolite (major)Metabolite (major)

HH3 3 CC

ConjugationConjugation

No effect on drugs studied:No effect on drugs studied:

– MethotrexateMethotrexate

– LithiumLithium

– GlyburideGlyburide

– WarfarinWarfarin

– PhenytoinPhenytoin

– TolbutamideTolbutamide

Drug-Drug InteractionsDrug-Drug Interactions

Incidence of GI Symptoms (>2%)Incidence of GI Symptoms (>2%)North American Controlled Arthritis TrialsNorth American Controlled Arthritis Trials

Celecoxib

AdverseEvent

Placebo 100 mgBID

200 mgQD

200 mgBID

NSAID

n 1864 1779 453 1914 2098

AbdominalPain

2.8 3.4 2.0 5.2 8.2†

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** placebo < celecoxib, p=0.008*** placebo < celecoxib, p=0.003

† celecoxib < NSAID, p=0.21‡ celecoxib < NSAID, p<0.001§ celecoxib < NSAID, p=0.002ƒ celecoxib < NSAID, p=0.003

Data on File: Searle

0.00

0.05

0.10

0.15

0.20

0.25

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

Cu

mu

lati

ve P

rob

ab

ility

NSAIDsn=2,427Celecoxibn=3,216Placebon=1,136

GI DiscomfortAbdominal Pain, Nausea, or

Dyspepsia

NSAIDs compared to Celecoxib, p<0.01Placebo 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-UsersRodriguez 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 Events6 Month Study (-041)

00

55

1010

1515

2020

2525

00 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424

Diclofenac SR 75mg BIDDiclofenac SR 75mg BID

Celecoxib 200mg BIDCelecoxib 200mg BID

%

% p

atie

nts

wit

hd

raw

np

atie

nts

wit

hd

raw

n

WeeksWeeksGeis GS et al. Geis GS et al. Arthritis & RheumArthritis & Rheum 1998;41(9) Suppl:1699A. 1998;41(9) Suppl:1699A. Data on File: Searle (Study 041)Data on File: Searle (Study 041)

p=0.001p=0.001

Celecoxib Allergic Reactions

Placebo(n= 1864)

Celecoxib(N=4146)

NSAID (n= 2098)

Rash 2.1 %2.1 % 2.2 %2.2 % 1.8 %1.8 %

Pruritus 1.7 %1.7 % 1.5 %1.5 % 1.2 %1.2 %

Urticaria 0.3 %0.3 % 0.5 %0.5 % 0.6 %0.6 %

Skin Disorder 0.3 %0.3 % 0.2 %0.2 % 0.6 %0.6 %

Searle: Data on file

112/04/08

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”

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。


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。


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 formulation; pregnancy

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 <1%: Hypotension, alopecia, maculopapular rash, aphthous stomatitis, arthralgias, which

include myalgias, rigors, retinopathy, dyspnea, rare hypersensitivity reactions

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 stomatitis are also seen

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 continuous bladder irrigation is rarely needed for doses <2 g/m2.

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-1CYP2B6, 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: 1. 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

2. Chloramphenicol results in prolonged cyclophosphamide half-life to increase toxicity

3. Cimetidine inhibits hepatic metabolism of drugs and may decrease or increase the activation of cyclophosphamide

Drug Interactions-3 Increased toxicity: 1. Doxorubicin: Cyclophosphamide may

enhance cardiac toxicity of anthracyclines 2. 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

3. 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.


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 DosageChildren: 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 DosageChildren 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, retinoids, sulfasalazine).

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 diseases and drugs.

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 proteins, increased MTX levels

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


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%


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

15-20 mg/m2P.O. Twice weekly

30-50 mg/m2P.O., I.V. Weekly

15 mg/day for 5 days P.O., I.M. Every 2-3 weeks

Intermediate

50-150 mg/m2I.V. push Every 2-3 weeks

240 mg/m2* I.V. infusion Every 4-7 days

0.5-1 g/m2* I.V. infusion Every 2-3 weeks

High

1-12 g/m2* 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 joint pain or other side effects you may experience.

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

SalicylazosulfapyridineDosage Forms Tablet: 500 mg Tablet, enteric coated: 500 mg

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 NSAIDsUse - Unlabeled/Investigational Ankylosing spondylitis, collagenous colitis, Crohn's disease, psoriasis, psoriatic arthritis, juvenile chronic arthritisPregnancy Risk Factor B/D (at term)

USE

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; pregnancy (at term)

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-1Azathioprine, 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 treatment)

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 until response to drug is known).

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 arthritisUse - Unlabeled/Investigational Porphyria cutanea tarda, polymorphous light eruptionsPregnancy Risk Factor CLactation Enters breast milk/compatibleContraindications Hypersensitivity to hydroxychloroquine, 4-aminoquinoline derivatives, or any component of the formulation; retinal or visual field changes attributable to 4-aminoquinolines


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-1CNS: 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-2Adults: 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

milkMonitoring Parameters Ophthalmologic exam, CBCDietary 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 reactions.

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 BALPregnancy Risk Factor DLactation Enters breast milk/contraindicated

ContraindicationsHypersensitivity 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, leukopenia

(2%), thrombocytopenia (4%)

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 administer with milk. Iron and zinc may decrease drug action.

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


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 therapy until numbers of platelets increase

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/capSolution 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

UseProphylaxis 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

ContraindicationsHypersensitivity 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.


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.


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 # Hypertention * # Neurologic changes* (tremor, numbness) Hirsutism* Gum hyperplasia* Electrolyte disturbance (↑K,↓Mg,↑uric acid )

Infection

(bacteria, viral, fungal) Hepatoxicity* Convulsions Thrombocytopenia & hemolytic anemia 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 (BRM)

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)ARHEUMA 雅努麻 ®

(Leflunomide)

Immuno-modulatorDMARD 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

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

Warnings

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

milkunknown) 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。

Algorithm for the aggressive treatment of rheumatoid at an early stage

ACTIVE DISEASE

EARLY DISEASELATE DISEASE

LOCALISED

SynovectomyIntra-articularJoint surgeryj

GENERALISEDGOOD PROGNOSIS

Hydroxychloroquine Sulfasalazine

PARTIAL RESPONSE orLOSS OF EFFICACY

Add other agents toExisting drug therapy

NO RESPONSETO THERAPY

Age ＜ 65 Age ＞ 65

Methotrexate or IM gold

RESPONSE TO THERAPY

Maintenance therapy with IM gold

Oral corticosteroid (low dose)

NO RESPONSE TO THERAPY

CyclosporinAzathioprineExerimental therapies

POOR PROGNOSIS

Pulse corticosteroid therapy

Pulse corticosteroid therapy

Documents

20070512 臨床治療學 - Rheumtoid Arthritis (RA)