پنیسیلامین
Penicillamine (Cuprimine)
پنیسیلامین

نام ژنریک

Penicillamine

شکل دارویی

اشكال دارويي:


Tablet: 250 mg


Capsule: 250 mg

موارد مصرف

موارد و مقدار مصرف


الف) بيماري ويلسون.


بزرگسالان: مقدار 250 ميلي‌گرم خوراکي چهار بار در روز، 60-30 دقيقه قبل از غذا و حداقل دو ساعت بعد از غذاي شب، مصرف مي‌شود. مقدار مصرف بايد طوري تنظيم شود كه دفع ادراري مس mg/day 1-5/0 باشد. مقدار مصرف بيش از دو گرم به ندرت ضروري است.


ب) وجود سيستين در ادرار (Cystinuria).


بزرگسالان: مقدار mg/day 250 خوراکي در چهار مقدار منقسم مصرف مي‌شود. سپس، مقدار مصرف به ‌تدريج افزايش مي‌يابد. مقدار معمول
مصرف g/day 2 (بين g/day 4-1) است. مقدار مصرف بايد طوري
تنظيم شود كه دفع ادراري سيستين كمتر از mg/day 100، در صورت
وجود سنگ كليه يا mg/day 200-100، در صورت عدم وجود سنگ كليه، باشد.


پ) آرتريت روماتوئيد، سندرم فلتي(Felty’s syndrome).


بزرگسالان:‌ ابتدا، مقدار mg/day 250-125 خوراکي مصرف مي‌شود و در صورت لزوم هر 3-1 ماه مقدار mg/day 250-125 به مقدار مصرف اضافه مي‌شود. حداكثر مقدار مصرف g/day 5/1 است.


ت) درمان كمكي در مسموميت با فلزات سنگين.


بزرگسالان: مقدار mg/day 1500-500 خوراکي به مدت 2-1 ماه مصرف مي‌شود.


ث) Primary biliary cirrhosis.


بزرگسالان: با 250 ميلي‌گرم خوراکي روزانه شروع شده و هر 2 هفته 250 ميلي‌گرم به آن اضافه مي‌شود. حداکثر مقدار مصرف 1 گرم روزانه در دوزهاي منقسم مي‌باشد.

موارد منع مصرف

موارد منع مصرف و احتياط


موارد منع مصرف: حساسيت مفرط شناخته شده به دارو، سابقه آگرانولوسيتوز يا كم‌خوني آپلاستيك وابسته به پني‌سيلامين، بي‌كفايتي قابل ملاحظه كليوي يا كبدي، دوران حاملگي، بيماراني كه املاح طلا، داروهاي سركوب كننده سيستم ايمني، ضد مالاريا، يا فنيل بوتازون مصرف مي‌كنند چراکه خطر بروز اثرات وخيم هماتولوژيك افزايش مي‌يابد.


موارد احتياط: حساسيت به پني‌سيلين (واكنش متقاطع به‌ندرت بروز مي‌كند)، بيماراني كه دورة دوم دارو را دريافت مي‌كنند (ممكن است به دارو حساس‌شده و به احتمال زياد دچار واكنش‌هاي آلرژيك شوند)، پروتئينوري كه ناشي از سندرم گودپاسچر (Good Pasture syndrome) نباشند.

عوارض جانبی دارو

عوارض جانبي


گوش، چشم، حلق، بيني: التهاب عمومي مخاط زبان، شقاق گوشه لبها، نوريت بينايي، زخمهاي دهاني، وزوز گوش.


پوست: آلوپسي، خارش، بثورات اريتماتوز، بثورات شديد خارش‌دار و پوسته‌دار، ضايعات ماكولي بر روي تنه، واكنش‌هاي پمفيگوئيد، كهير، درماتيت اكسفولياتيو، افزايش شكنندگي پوست، اكيموز پورپورايي يا وزيكولي، چروكيدگي پوست.


دستگاه گوارش: بي‌اشتهايي، تهوع، استفراغ، سوء هاضمه، اسهال، اختلال در حس چشايي، پانکراتيت


ادراري ـ تناسلي: پروتئينوري.


خون: ائوزينوفيلي، لكوپني، ترومبوسيتوپني، كم‌خوني آپلاستيك، آگرانولوسيتوز، ترومبوتيک ترومبوسيتوپنيك پورپورا، كم‌خوني يا كم‌خوني فقر آهن، سندرم هموليتيک شبه لوپوس، ساپرس شدن مغز استخوان.


كبدي: يرقان انسدادي، اختلال كار كبد.


متابوليک: تيروئيديت.


عضلاني- اسکلتي : آرترالژي، مياستني گراويس.


تنفسي: سندروم گودپاسچر، پنومونايتيس، پنوموني.


ساير عوارض: لنفادنوپاتي، تب دارويي


مسموميت و درمان


تظاهرات باليني: هيچ‌گونه گزارشي در مورد مصرف بيش از حد اين دارو وجود ندارد.


درمان: در صورت هوشيار بودن بيمار يا سالم بودن بازتاب حلقي (gag reflex) با تحريك استفراغ معده را تخليه مي‌كنند. در غير اين صورت، معده را با شستشو تخليه كرده و سپس زغال فعال و سوربيتول تجويز مي‌كنند. بعد از آن، بيمار به طور حمايتي درمان مي‌شود. حملات تشنجي با ديازپام (يا پيريدوكسين، در صورتي كه استفاده قبلي از آن موفقيت‌آميز بوده) درمان مي‌شود. همودياليز موجب دفع پني‌سيلامين خواهد شد.

موارد قابل توجه

-

تداخل دارویی

تداخل دارويي


املاح آهن و ضد اسيدها جذب پني‌سيلامين را كاهش مي‌دهند. دوزها از يکديگر جدا شوند.


استفاده توام با ضد مالارياها، داروهاي سايتوتوکسيک، طلا، اکسي فن بوتازون و فنيل بوتازون ممکن است اثرات هماتولوژيک و کليوي جدي ايجاد کند. از مصرف توام خودداري شود.


استفاده توام با ديگوکسين ممکن است سطح سرمي ديگوکسين را افزايش دهد.

مکانیزم اثر

تداخل دارويي


املاح آهن و ضد اسيدها جذب پني‌سيلامين را كاهش مي‌دهند. دوزها از يکديگر جدا شوند.


استفاده توام با ضد مالارياها، داروهاي سايتوتوکسيک، طلا، اکسي فن بوتازون و فنيل بوتازون ممکن است اثرات هماتولوژيک و کليوي جدي ايجاد کند. از مصرف توام خودداري شود.


استفاده توام با ديگوکسين ممکن است سطح سرمي ديگوکسين را افزايش دهد.

فارماكوكینتیك

فارماكوكينتيك


جذب: از دستگاه گوارش به‌خوبي جذب مي‌شود.


پخش: اتصال پروتئيني آن حدود 80% مي‌باشد.


متابوليسم: بوسيله كبد به ترکيبات غيرفعال متابوليزه مي‌شود.


دفع: فقط مقدار كمي از پني‌سيلامين به صورت تغيير نيافته دفع مي‌شود. بعد از 24 ساعت، حدود 50% از راه ادرار و 50% از راه مدفوع دفع مي‌شود.





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نامشخص



سایر اطلاعات

طبقه‌بندي فارماكولوژيك: داروي شلات كننده.


طبقه‌بندي درماني: آنتاگونيست فلزات سنگين، ضد روماتيسم.


طبقه‌بندي مصرف در بارداري: گزارش نشده است.


نام‌هاي تجاري: Artamin,Cupripen


ملاحظات اختصاصي


1- در صورت بروز موارد زير بايد مصرف دارو قطع شود: بروز علائم حساسيت مفرط يا تب دارويي، معمولاً همراه با ساير تظاهرات آلرژيك (در صورت بيماري ويلسون، ممكن است دارو مجدداً مورد مصرف قرار گيرد)، بروز بثورات پوستي شش ماه يا بيشتر بعد از شروع درمان، واكنش پمفيگوئيد، هماچوري يا پروتئينوري همراه با هموپتزي يا انفيلتراسيون ريوي، هماچوري يا پروتئينوري مداوم بيش از g/day 2 در بيماران مبتلا به آرتريت روماتوئيد، در صورتي كه تعداد پلاكتها كمتر از mm3/100000 يا تعداد گلبولهاي سفيد كمتر ازmm3/3500 باشد يااينكه در سه آزمون متوالي اين عناصر خوني مشاهده شود(حتي اگر در حد طبيعي باشند).


2- آزمونهاي عملكرد كبد و كليه معمولاً هر شش ماه انجام مي‌شود. بيمار بايد از نظر پروتئينوري به طور معمول بررسي و براي جلوگيري از صدمات پوستي، به‌دقت مراقبت شود.


3- در بيماران مبتلا به بيماري ويلسون يا سيستينوري ممكن است مصرف روزانه پيريدوكسين (ويتامين B6) ضروري باشد.


4- مصرف پني‌سيلامين يك ساعت قبل يا دو ساعت بعد از غذا يا داروهاي ديگر موجب تسهيل جذب دارو خواهد شد.


5- در درمان اوليه بيماري ويلسون، بايد همراه با پني‌سيلامين به‌ مدت شش‌ماه تا يك سال با هر وعده غذا مقدار 40-10 ميلي‌گرم پتاش سولفوره مصرف شده و سپس قطع ‌شود.


6- درمان دارويي ممکن است منجر به مثبت شدن نتايج تست ANA، با يا بدون علائم باليني سندروم شبه لوپوس اريتماتوز شود.


7- همودياليز مي‌تواند پني سيلامين را برداشت کند.


نكات قابل توصيه به بيمار


1- در ارتباط با بيماري ويلسون، آرتريت روماتوئيد يا سيستينوري اطلاعات کافي به بيماران بدهيد و پروسه بيماري و منطق درمان را کاملا توضيح دهيد. اثرات باليني دارو ممكن است تا سه ماه آشكار نشود.


2- دارو را طبق دستور مصرف و به طور مرتب به پزشك مراجعه كنيد.


3- در صورت بروز تب، لرز، گلودرد، كبودي، خونريزي يا واكنش آلرژيك، فوراً به پزشك اطلاع دهيد.


4- دارو را با معده خالي، 60-30 دقيقه قبل از غذا يا دو ساعت بعد از غذا، ضد اسيدها، مكملهاي معدني، ويتامينها يا داروهاي ديگر مصرف كنيد. مقدار زيادي آب، بخصوص در شب، بنوشيد.


5- در صورت مصرف پني‌سيلامين براي درمان آرتريت روماتوئيد، ممكن است در طول درمان بيماري تشديد شود. اين حالت را معمولاً مي‌توان با مصرف همزمان داروهاي ضد التهاب غيراستروئيدي كنترل كرد.


6- در صورت مصرف پني‌سيلامين براي درمان بيماري ويلسون، از رژيم غذايي حاوي مس كم (كمتر از mg/day 2 ) تبعيت كنيد. به اين منظور از مصرف غذاهاي حاوي مس زياد مانند شكلات، آجيل، بروکلي و جگر خودداري نماييد. همچنين جهت کاهش جذب مس ممکن است پتاش سولفوره با غذا مصرف شود.


مصرف در سالمندان: در بيماران سالخورده ممكن است به مقادير كمتر مصرف احتياج باشد. عملكرد كليوي و كبدي اين بيماران بايد به‌دقت پيگيري شود. سميت دارويي در بيماران مسن شايعتر مي‌باشد.


مصرف در كودكان: احتمال بروز فقر آهن ناشي از مصرف طولاني‌مدت دارو بايد در نظر گرفته شود. بي ضرري و کارايي مصرف دارو در آرتريت روماتوئيد juvenile اثبات نشده است.


مصرف در شيردهي: وجود دارو در شير نامشخص بوده و بي‌ضرري مصرف دارو در دوران شيردهي ثابت نشده است. شيردهي در دوران مصرف اين دارو توصيه نمي‌شود.


اثر بر آزمايشهاي تشخيصي


پني‌سيلامين ممكن است سطح آنزيمهاي کبدي را افزايش و سطح هموگلوبين را کاهش دهد.


ممکن است شمارش ائوزينوفيل را افزايش و هماتوکريت، گرانولوسيت، پلاکت و شمارش گلوبول سفيد را کاهش دهد.

Penicillamine (Cuprimine)

CUPRIMINE®
(penicillamine) Capsules

Physicians planning to use penicillamine should thoroughly familiarize themselves with its toxicity, special dosage considerations, and therapeutic benefits. Penicillamine should never be used casually. Each patient should remain constantly under the close supervision of the physician. Patients should be warned to report promptly any symptoms suggesting toxicity.

DRUG DESCRIPTION

Penicillamine is a chelating agent used in the treatment of Wilson's disease. It is also used to reduce cystine excretion in cystinuria and to treat patients with severe, active rheumatoid arthritis unresponsive to conventional therapy (see INDICATIONS). It is 3-mercapto-D-valine. It is a white or practically white, crystalline powder, freely soluble in water, slightly soluble in alcohol, and insoluble in ether, acetone, benzene, and carbon tetrachloride. Although its configuration is D, it is levorotatory as usually measured:

[α] 25°= -62.5° ± 2° (c = 1, 1N NaOH), D
calculated on a dried basis.

The empirical formula is C5H11NO2S, giving it a molecular weight of 149.21. The structural formula is:

CUPRIMINE® (Penicillamine) Structural Formula Illustration

It reacts readily with formaldehyde or acetone to form a thiazolidine-carboxylic acid. Capsules CUPRIMINE* (Penicillamine) for oral administration contain either 125 mg or 250 mg of penicillamine. Each capsule contains the following inactive ingredients: D & C Yellow 10, gelatin, lactose, magnesium stearate, and titanium dioxide. The 125 mg capsule also contains iron oxide.

What are the possible side effects of penicillamine (Cuprimine, Depen)?

If you experience any of the following serious side effects, seek emergency medical attention or contact your doctor immediately:

  • an allergic reaction (shortness of breath; closing of your throat; difficulty breathing; swelling of your lips, face, or tongue; or hives);
  • fever or chills;
  • a sore throat;
  • unusual bleeding or bruising;
  • blood in the urine;
  • unexplained shortness of breath, coughing, or wheezing;
  • abdominal pain;
  • yellow skin or eyes;
  • muscle weakness; or
  • double vision.

Other, less...

Read All Potential Side Effects and See Pictures of Cuprimine »

What are the precautions when taking penicillamine (Cuprimine)?

Before taking penicillamine, tell your doctor or pharmacist if you are allergic to it; or to penicillins; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: a previous severe reaction to penicillamine (such as aplastic anemia, agranulocytosis), kidney disease, blood/bone marrow disorders (such as thrombocytopenia).

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

Penicillamine is not recommended for use during pregnancy. It may harm an...

Read All Potential Precautions of Cuprimine »

Last reviewed on RxList: 12/17/2008
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

CUPRIMINE (penicillamine) is indicated in the treatment of Wilson's disease, cystinuria, and in patients with severe, active rheumatoid arthritis who have failed to respond to an adequate trial of conventional therapy. Available evidence suggests that CUPRIMINE (penicillamine) is not of value in ankylosing spondylitis.

Wilson's Disease — Wilson's disease (hepatolenticular degeneration) occurs in individuals who have inherited an autosomal recessive defect that leads to an accumulation of copper far in excess of metabolic requirements. The excess copper is deposited in several organs and tissues, and eventually produces pathological effects primarily in the liver, where damage progresses to postnecrotic cirrhosis, and in the brain, where degeneration is widespread. Copper is also deposited as characteristic, asymptomatic, golden-brown Kayser-Fleischer rings in the corneas of all patients with cerebral symptomatology and some patients who are either asymptomatic or manifest only hepatic symptomatology.

Two types of patients require treatment for Wilson's disease: (1) the symptomatic, and (2) the asymptomatic in whom it can be assumed the disease will develop in the future if the patient is not treated.

The diagnosis, if suspected on the basis of family or individual history or physical examination, can be confirmed if the plasma copper-protein ceruloplasmin** is < 20 mg/dL and either a quantitative determination in a liver biopsy specimen shows an abnormally high concentration of copper ( > 250 mcg/g dry weight) or Kayser-Fleischer rings are present.

Treatment has two objectives:

  1. to minimize dietary intake of copper;
  2. to promote excretion and complex formation (i.e., detoxification) of excess tissue copper.

The first objective is attained by a daily diet that contains no more than one or two milligrams of copper. Such a diet should exclude, most importantly, chocolate, nuts, shellfish, mushrooms, liver, molasses, broccoli, and cereals and dietary supplements enriched with copper, and be composed to as great an extent as possible of foods with a low copper content. Distilled or demineralized water should be used if the patient's drinking water contains more than 0.1 mg of copper per liter.

For the second objective, a copper chelating agent is used.

In symptomatic patients this treatment usually produces marked neurologic improvement, fading of Kayser-Fleischer rings, and gradual amelioration of hepatic dysfunction and psychic disturbances.

Clinical experience to date suggests that life is prolonged with the above regimen.

Noticeable improvement may not occur for one to three months. Occasionally, neurologic symptoms become worse during initiation of therapy with CUPRIMINE (penicillamine) . Despite this, the drug should not be withdrawn. Temporary interruption carries an increased risk of developing a sensitivity reaction upon resumption of therapy, although it may result in clinical improvement of neurological symptoms (see WARNINGS). If the neurological symptoms and signs continue to worsen for a month after the initiation of CUPRIMINE (penicillamine) therapy, several short courses of treatment with 2,3 - dimercaprol (BAL) while continuing CUPRIMINE (penicillamine) may be considered.

Treatment of asymptomatic patients has been carried out for over thirty years. Symptoms and signs of the disease appear to be prevented indefinitely if daily treatment with CUPRIMINE (penicillamine) is continued.

Cystinuria - Cystinuria is characterized by excessive urinary excretion of the dibasic amino acids, arginine, lysine, ornithine, and cystine, and the mixed disulfide of cysteine and homocysteine. The metabolic defect that leads to cystinuria is inherited as an autosomal, recessive trait. Metabolism of the affected amino acids is influenced by at least two abnormal factors: (1) defective gastrointestinal absorption and (2) renal tubular dysfunction.

Arginine, lysine, ornithine, and cysteine are soluble substances, readily excreted. There is no apparent pathology connected with their excretion in excessive quantities.

Cystine, however, is so slightly soluble at the usual range of urinary pH that it is not excreted readily, and so crystallizes and forms stones in the urinary tract. Stone formation is the only known pathology in cystinuria.

Normal daily output of cystine is 40 to 80 mg. In cystinuria, output is greatly increased and may exceed 1 g/day. At 500 to 600 mg/day, stone formation is almost certain. When it is more than 300 mg/day, treatment is indicated.

Conventional treatment is directed at keeping urinary cystine diluted enough to prevent stone formation, keeping the urine alkaline enough to dissolve as much cystine as possible, and minimizing cystine production by a diet low in methionine (the major dietary precursor of cystine). Patients must drink enough fluid to keep urine specific gravity below 1.010, take enough alkali to keep urinary pH at 7.5 to 8, and maintain a diet low in methionine. This diet is not recommended in growing children and probably is contraindicated in pregnancy because of its low protein content (see PRECAUTIONS).

When these measures are inadequate to control recurrent stone formation, CUPRIMINE (penicillamine) may be used as additional therapy, and when patients refuse to adhere to conventional treatment, CUPRIMINE (penicillamine) may be a useful substitute. It is capable of keeping cystine excretion to near normal values, thereby hindering stone formation and the serious consequences of pyelonephritis and impaired renal function that develop in some patients. Bartter and colleagues depict the process by which penicillamine interacts with cystine to form penicillamine-cysteine mixed disulfide as:

Penicillamine interaction  with cystine - illustration

CSSC = cystine

CS' = deprotonated

cysteine PSSP = penicillamine disulfide

PS' = deprotonated penicillamine sulfhydryl

CSSP = penicillamine-cysteine mixed disulfide

In this process, it is assumed that the deprotonated form of penicillamine, PS', is the active factor in bringing about the disulfide interchange.

Rheumatoid Arthritis — Because CUPRIMINE (penicillamine) can cause severe adverse reactions, its use in rheumatoid arthritis should be restricted to patients who have severe, active disease and who have failed to respond to an adequate trial of conventional therapy. Even then, benefit-to-risk ratio should be carefully considered. Other measures, such as rest, physiotherapy, salicylates, and corticosteroids should be used, when indicated, in conjunction with CUPRIMINE (see PRECAUTIONS).

DOSAGE AND ADMINISTRATION

In all patients receiving penicillamine, it is important that CUPRIMINE (penicillamine) be given on an empty stomach, at least one hour before meals or two hours after meals, and at least one hour apart from any other drug, food, or milk. Because penicillamine increases the requirement for pyridoxine, patients may require a daily supplement of pyridoxine (see PRECAUTIONS).

Wilson's Disease — Optimal dosage can be determined by measurement of urinary copper excretion and the determination of free copper in the serum. The urine must be collected in copper-free glassware, and should be quantitatively analyzed for copper before and soon after initiation of therapy with CUPRIMINE (penicillamine) .

Determination of 24-hour urinary copper excretion is of greatest value in the first week of therapy with penicillamine. In the absence of any drug reaction, a dose between 0.75 and 1.5 g that results in an initial 24-hour cupriuresis of over 2 mg should be continued for about three months, by which time the most reliable method of monitoring maintenance treatment is the determination of free copper in the serum. This equals the difference between quantitatively determined total copper and ceruloplasmin-copper. Adequately treated patients will usually have less than 10 mcg free copper/dL of serum. It is seldom necessary to exceed a dosage of 2 g/day. If the patient is intolerant to therapy with CUPRIMINE (penicillamine) , alternative treatment is trientine hydrochloride.

In patients who cannot tolerate as much as 1 g/day initially, initiating dosage with 250 mg/day, and increasing gradually to the requisite amount, gives closer control of the effects of the drug and may help to reduce the incidence of adverse reactions.

Cystinuria — It is recommended that CUPRIMINE (penicillamine) be used along with conventional therapy. By reducing urinary cystine, it decreases crystalluria and stone formation. In some instances, it has been reported to decrease the size of, and even to dissolve, stones already formed.

The usual dosage of CUPRIMINE (penicillamine) in the treatment of cystinuria is 2 g/day for adults, with a range of 1 to 4 g/day. For pediatric patients, dosage can be based on 30 mg/kg/day. The total daily amount should be divided into four doses. If four equal doses are not feasible, give the larger portion at bedtime. If adverse reactions necessitate a reduction in dosage, it is important to retain the bedtime dose.

Initiating dosage with 250 mg/day, and increasing gradually to the requisite amount, gives closer control of the effects of the drug and may help to reduce the incidence of adverse reactions. In addition to taking CUPRIMINE (penicillamine) , patients should drink copiously. It is especially important to drink about a pint of fluid at bedtime and another pint once during the night when urine is more concentrated and more acid than during the day. The greater the fluid intake, the lower the required dosage of CUPRIMINE (penicillamine) .

Dosage must be individualized to an amount that limits cystine excretion to 100-200 mg/day in those with no history of stones, and below 100 mg/day in those who have had stone formation and/or pain. Thus, in determining dosage, the inherent tubular defect, the patient's size, age, and rate of growth, and his diet and water intake all must be taken into consideration.

The standard nitroprusside cyanide test has been reported useful as a qualitative measure of the effective dose:†Add 2 mL of freshly prepared 5 percent sodium cyanide to 5 mL of a 24-hour aliquot of protein-free urine and let stand ten minutes. Add 5 drops of freshly prepared 5 percent sodium nitroprusside and mix. Cystine will turn the mixture magenta. If the result is negative, it can be assumed that cystine excretion is less than 100 mg/g creatinine.

Although penicillamine is rarely excreted unchanged, it also will turn the mixture magenta.If there is any question as to which substance is causing the reaction, a ferric chloride test can be done to eliminate doubt: Add 3 percent ferric chloride dropwise to the urine. Penicillamine will turn the urine an immediate and quickly fading blue. Cystine will not produce any change in appearance.

Rheumatoid Arthritis — The principal rule of treatment with CUPRIMINE (penicillamine) in rheumatoid arthritis is patience. The onset of therapeutic response is typically delayed. Two or three months may be required before the first evidence of a clinical response is noted (see CLINICAL PHARMACOLOGY).

When treatment with CUPRIMINE (penicillamine) has been interrupted because of adverse reactions or other reasons, the drug should be reintroduced cautiously by starting with a lower dosage and increasing slowly.

Initial Therapy — The currently recommended dosage regimen in rheumatoid arthritis begins with a single daily dose of 125 mg or 250 mg, which is thereafter increased at one to three month intervals, by 125 mg or 250 mg/day, as patient response and tolerance indicate. If a satisfactory remission of symptoms is achieved, the dose associated with the remission should be continued (see Maintenance Therapy). If there is no improvement and there are no signs of potentially serious toxicity after two to three months of treatment with doses of 500-750 mg/day, increases of 250 mg/day at two to three month intervals may be continued until a satisfactory remission occurs (see Maintenance Therapy) or signs of toxicity develop (see WARNINGS and PRECAUTIONS). If there is no discernible improvement after three to four months of treatment with 1000 to 1500 mg of penicillamine/day, it may be assumed the patient will not respond and CUPRIMINE (penicillamine) should be discontinued.

Maintenance Therapy — The maintenance dosage of CUPRIMINE (penicillamine) must be individualized, and may require adjustment during the course of treatment. Many patients respond satisfactorily to a dosage within the 500-750 mg/day range. Some need less.

Changes in maintenance dosage levels may not be reflected clinically or in the erythrocyte sedimentation rate for two to three months after each dosage adjustment.

Some patients will subsequently require an increase in the maintenance dosage to achieve maximal disease suppression. In those patients who do respond, but who evidence incomplete suppression of their disease after the first six to nine months of treatment, the daily dosage of CUPRIMINE (penicillamine) may be increased by 125 mg or 250 mg/day at three-month intervals. It is unusual in current practice to employ a dosage in excess of 1 g/day, but up to 1.5 g/day has sometimes been required.

Management of Exacerbations — During the course of treatment some patients may experience an exacerbation of disease activity following an initial good response. These may be self-limited and can subside within twelve weeks. They are usually controlled by the addition of non-steroidal antiinflammatory drugs, and only if the patient has demonstrated a true "escape" phenomenon (as evidenced by failure of the flare to subside within this time period) should an increase in the maintenance dose ordinarily be considered.

In the rheumatoid patient, migratory polyarthralgia due to penicillamine is extremely difficult to differentiate from an exacerbation of the rheumatoid arthritis. Discontinuance or a substantial reduction in dosage of CUPRIMINE (penicillamine) for up to several weeks will usually determine which of these processes is responsible for the arthralgia.

Duration of Therapy — The optimum duration of therapy with CUPRIMINE (penicillamine) in rheumatoid arthritis has not been determined. If the patient has been in remission for six months or more, a gradual, stepwise dosage reduction in decrements of 125 mg or 250 mg/day at approximately three month intervals may be attempted.

Concomitant Drug Therapy — CUPRIMINE (penicillamine) should not be used in patients who are receiving gold therapy, antimalarial or cytotoxic drugs, oxyphenbutazone, or phenylbutazone (see PRECAUTIONS). Other measures, such as salicylates, other non-steroidal anti-inflammatory drugs, or systemic corticosteroids, may be continued when penicillamine is initiated. After improvement commences, analgesic and anti-inflammatory drugs may be slowly discontinued as symptoms permit. Steroid withdrawal must be done gradually, and many months of treatment with CUPRIMINE (penicillamine) may be required before steroids can be completely eliminated.

Dosage Frequency — Based on clinical experience, dosages up to 500 mg/day can be given as a single daily dose. Dosages in excess of 500 mg/day should be administered in divided doses.

HOW SUPPLIED

Capsules CUPRIMINE (penicillamine) , 250 mg, are ivory-colored capsules containing a white or nearly white powder, and are coded CUPRIMINE (penicillamine) and MSD 602. They are supplied as follows: NDC 25010-705-15 in bottles of 100.

Storage

Keep container tightly closed.

REFERENCES

** For quantitative test for serum ceruloplasmin see: Morell, A.G.; Windsor, J.; Sternlieb, I. ; Scheinberg, I.H.: Measurement of the concentration of ceruloplasmin in serum by determination of its oxidase activity, in “Laboratory Diagnosis of Liver Disease”, F.W. Sunderman; F.W. Sunderman, Jr. (eds.), St. Louis, Warren H. Green, Inc., 1968, pp. 193-195.

†Lotz, M.; Potts, J.T. and Bartter, F.C.: Brit. Med. J. 2: 521, Aug. 28, 1965 (in Medical Memoranda).

Distributed by: Aton Pharma, Lawrenceville NJ 08648, USA. Manufactured by: Merck and Co., Inc. West Point, PA 19486, USA. Issued May 2007. FDA revision date: 10/26/2004

Last reviewed on RxList: 12/17/2008
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

Penicillamine is a drug with a high incidence of untoward reactions, some of which are potentially fatal. Therefore, it is mandatory that patients receiving penicillamine therapy remain under close medical supervision throughout the period of drug administration (see WARNINGS and PRECAUTIONS).

Reported incidences (%) for the most commonly occurring adverse reactions in rheumatoid arthritis patients are noted, based on 17 representative clinical trials reported in the literature (1270 patients).

Allergic — Generalized pruritus, early and late rashes (5%), pemphigus (see WARNINGS), and drug eruptions which may be accompanied by fever, arthralgia, or lymphadenopathy have occurred (see WARNINGS and PRECAUTIONS). Some patients may show a lupus erythematosus-like syndrome similar to drug-induced lupus produced by other pharmacological agents (see PRECAUTIONS).

Urticaria and exfoliative dermatitis have occurred.

Thyroiditis has been reported; hypoglycemia in association with anti-insulin antibodies has been reported. These reactions are extremely rare.

Some patients may develop a migratory polyarthralgia, often with objective synovitis (see DOSAGE AND ADMINISTRATION).

GastrointestinalAnorexia, epigastric pain, nausea, vomiting, or occasional diarrhea may occur (17%).

Isolated cases of reactivated peptic ulcer have occurred, as have hepatic dysfunction including hepatic failure, and pancreatitis. Intrahepatic cholestasis and toxic hepatitis have been reported rarely. There have been a few reports of increased serum alkaline phosphatase, lactic dehydrogenase, and positive cephalin flocculation and thymol turbidity tests.

Some patients may report a blunting, diminution, or total loss of taste perception (12%); or may develop oral ulcerations. Although rare, cheilosis, glossitis, and gingivostomatitis have been reported (see PRECAUTIONS).

Gastrointestinal side effects are usually reversible following cessation of therapy.

Hematological — Penicillamine can cause bone marrow depression (see WARNINGS). Leukopenia (2%) and thrombocytopenia (4%) have occurred. Fatalities have been reported as a result of thrombocytopenia, agranulocytosis, aplastic anemia, and sideroblastic anemia.

Thrombotic thrombocytopenic purpura, hemolytic anemia, red cell aplasia, monocytosis, leukocytosis, eosinophilia, and thrombocytosis have also been reported.

Renal — Patients on penicillamine therapy may develop proteinuria (6%) and/or hematuria which, in some, may progress to the development of the nephrotic syndrome as a result of an immune complex membranous glomerulopathy (see WARNINGS). Renal failure has been reported.

Central Nervous SystemTinnitus, optic neuritis and peripheral sensory and motor neuropathies (including polyradiculoneuropathy, i.e., Guillain-Barré syndrome) have been reported. Muscular weakness may or may not occur with the peripheral neuropathies. Visual and psychic disturbances; mental disorders; and agitation and anxiety have been reported.

NeuromuscularMyasthenia gravis (see WARNINGS); dystonia.

Other — Adverse reactions that have been reported rarely include thrombophlebitis; hyperpyrexia (see PRECAUTIONS); falling hair or alopecia; lichen planus; polymyositis; dermatomyositis; mammary hyperplasia; elastosis perforans serpiginosa; toxic epidermal necrolysis; anetoderma (cutaneous macular atrophy); and Goodpasture's syndrome, a severe and ultimately fatal glomerulonephritis associated with intra-alveolar hemorrhage (see WARNINGS). Vasculitis, including fatal renal vasculitis, has also been reported. Allergic alveolitis, obliterative bronchiolitis, interstitial pneumonitis and pulmonary fibrosis have been reported in patients with severe rheumatoid arthritis, some of whom were receiving penicillamine. Bronchial asthma also has been reported.

Increased skin friability, excessive wrinkling of skin, and development of small white papules at venipuncture and surgical sites have been reported (see PRECAUTIONS); yellow nail syndrome.

The chelating action of the drug may cause increased excretion of other heavy metals such as zinc, mercury and lead.

There have been reports associating penicillamine with leukemia. However, circumstances involved in these reports are such that a cause and effect relationship to the drug has not been established.

Read the Cuprimine (penicillamine) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

No information provided.

Last reviewed on RxList: 12/17/2008
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

The use of penicillamine has been associated with fatalities due to certain diseases such as aplastic anemia, agranulocytosis, thrombocytopenia, Goodpasture's syndrome, and myasthenia gravis.

Because of the potential for serious hematological and renal adverse reactions to occur at any time, routine urinalysis, white and differential blood cell count, hemoglobin determination, and direct platelet count must be done twice weekly, together with monitoring of the patient's skin, lymph nodes and body temperature, during the first month of therapy, every two weeks for the next five months, and monthly thereafter. Patients should be instructed to report promptly the development of signs and symptoms of granulocytopenia and/or thrombocytopenia such as fever, sore throat, chills, bruising or bleeding. The above laboratory studies should then be promptly repeated. Leukopenia and thrombocytopenia have been reported to occur in up to five percent of patients during penicillamine therapy.

Leukopenia is of the granulocytic series and may or may not be associated with an increase in eosinophils. A confirmed reduction in WBC below 3500/mm³ mandates discontinuance of penicillamine therapy. Thrombocytopenia may be on an idiosyncratic basis, with decreased or absent megakaryocytes in the marrow, when it is part of an aplastic anemia. In other cases the thrombocytopenia is presumably on an immune basis since the number of megakaryocytes in the marrow has been reported to be normal or sometimes increased. The development of a platelet count below 100,000/mm³, even in the absence of clinical bleeding, requires at least temporary cessation of penicillamine therapy. A progressive fall in either platelet count or WBC in three successive determinations, even though values are still within the normal range, likewise requires at least temporary cessation.

Proteinuria and/or hematuria may develop during therapy and may be warning signs of membranous glomerulopathy which can progress to a nephrotic syndrome. Close observation of these patients is essential. In some patients the proteinuria disappears with continued therapy; in others, penicillamine must be discontinued. When a patient develops proteinuria or hematuria the physician must ascertain whether it is a sign of drug-induced glomerulopathy or is unrelated to penicillamine.

Rheumatoid arthritis patients who develop moderate degrees of proteinuria may be continued cautiously on penicillamine therapy, provided that quantitative 24-hour urinary protein determinations are obtained at intervals of one to two weeks. Penicillamine dosage should not be increased under these circumstances. Proteinuria which exceeds 1 g/24 hours, or proteinuria which is progressively increasing, requires either discontinuance of the drug or a reduction in the dosage. In some patients, proteinuria has been reported to clear following reduction in dosage.

In rheumatoid arthritis patients penicillamine should be discontinued if unexplained gross hematuria or persistent microscopic hematuria develops.

In patients with Wilson's disease or cystinuria the risks of continued penicillamine therapy in patients manifesting potentially serious urinary abnormalities must be weighed against the expected therapeutic benefits.

When penicillamine is used in cystinuria, an annual x-ray for renal stones is advised. Cystine stones form rapidly, sometimes in six months. Up to one year or more may be required for any urinary abnormalities to disappear after penicillamine has been discontinued.

Because of rare reports of intrahepatic cholestasis and toxic hepatitis, liver function tests are recommended every six months for the duration of therapy. In Wilson's disease, these are recommended every three months, at least during the first year of treatment.

Goodpasture's syndrome has occurred rarely. The development of abnormal urinary findings associated with hemoptysis and pulmonary infiltrates on x-ray requires immediate cessation of penicillamine.

Obliterative bronchiolitis has been reported rarely. The patient should be cautioned to report immediately pulmonary symptoms such as exertional dyspnea, unexplained cough or wheezing. Pulmonary function studies should be considered at that time.

Onset of new neurological symptoms has been reported with CUPRIMINE (see ADVERSE REACTIONS). Occasionally, neurological symptoms become worse during initiation of therapy with CUPRIMINE (see INDICATIONS). Myasthenic syndrome sometimes progressing to myasthenia gravis has been reported. Ptosis and diplopia, with weakness of the extraocular muscles, are often early signs of myasthenia. In the majority of cases, symptoms of myasthenia have receded after withdrawal of penicillamine.

Most of the various forms of pemphigus have occurred during treatment with penicillamine. Pemphigus vulgaris and pemphigus foliaceus are reported most frequently, usually as a late complication of therapy. The seborrhea-like characteristics of pemphigus foliaceus may obscure an early diagnosis. When pemphigus is suspected, CUPRIMINE (penicillamine) should be discontinued. Treatment has consisted of high doses of corticosteroids alone or, in some cases, concomitantly with an immunosuppressant. Treatment may be required for only a few weeks or months, but may need to be continued for more than a year.

Once instituted for Wilson's disease or cystinuria, treatment with penicillamine should, as a rule, be continued on a daily basis. Interruptions for even a few days have been followed by sensitivity reactions after reinstitution of therapy.

Pregnancy Category D

Penicillamine can cause fetal harm when administered to a pregnant woman. Penicillamine has been shown to be teratogenic in rats when given in doses 6 times higher than the highest dose recommended for human use. Skeletal defects, cleft palates and fetal toxicity (resorptions) have been reported.

There are no controlled studies on the use of penicillamine in pregnant women. Although normal outcomes have been reported, characteristic congenital cutis laxa and associated birth defects have been reported in infants born of mothers who received therapy with penicillamine during pregnancy. Penicillamine should be used in women of childbearing potential only when the expected benefits outweigh the possible hazards. Women on therapy with penicillamine who are of childbearing potential should be apprised of this risk, advised to report promptly any missed menstrual periods or other indications of possible pregnancy, and followed closely for early recognition of pregnancy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Wilson's Disease — Reported experience*** shows that continued treatment with penicillamine throughout pregnancy protects the mother against relapse of the Wilson's disease, and that discontinuation of penicillamine has deleterious effects on the mother, which may be fatal.

If penicillamine is administered during pregnancy to patients with Wilson's disease, it is recommended that the daily dosage be limited to 750 mg. If cesarean section is planned the daily dose should be reduced to 250 mg, but not lower, for the last six weeks of pregnancy and postoperatively until wound healing is complete.

Cystinuria— If possible, penicillamine should not be given during pregnancy to women with cystinuria (see CONTRAINDICATIONS). There are reports of women with cystinuria on therapy with penicillamine who gave birth to infants with generalized connective tissue defects who died following abdominal surgery. If stones continue to form in these patients, the benefits of therapy to the mother must be evaluated against the risk to the fetus.

Rheumatoid Arthritis — Penicillamine should not be administered to rheumatoid arthritis patients who are pregnant (see CONTRAINDICATIONS) and should be discontinued promptly in patients in whom pregnancy is suspected or diagnosed. There is a report that a woman with rheumatoid arthritis treated with less than one gram a day of penicillamine during pregnancy gave birth (cesarean delivery) to an infant with growth retardation, flattened face with broad nasal bridge, low set ears, short neck with loose skin folds, and unusually lax body skin.

PRECAUTIONS

Some patients may experience drug fever, a marked febrile response to penicillamine, usually in the second to third week following initiation of therapy. Drug fever may sometimes be accompanied by a macular cutaneous eruption. In the case of drug fever in patients with Wilson's disease or cystinuria, penicillamine should be temporarily discontinued until the reaction subsides. Then penicillamine should be reinstituted with a small dose that is gradually increased until the desired dosage is attained. Systemic steroid therapy may be necessary, and is usually helpful, in such patients in whom drug fever and rash develop several times.

In the case of drug fever in rheumatoid arthritis patients, because other treatments are available, penicillamine should be discontinued and another therapeutic alternative tried since experience indicates that the febrile reaction will recur in a very high percentage of patients upon readministration of penicillamine.

The skin and mucous membranes should be observed for allergic reactions. Early and late rashes have occurred. Early rash occurs during the first few months of treatment and is more common. It is usually a generalized pruritic, erythematous, maculopapular or morbilliform rash and resembles the allergic rash seen with other drugs. Early rash usually disappears within days after stopping penicillamine and seldom recurs when the drug is restarted at a lower dosage. Pruritus and early rash may often be controlled by the concomitant administration of antihistamines. Less commonly, a late rash may be seen, usually after six months or more of treatment, and requires discontinuation of penicillamine. It is usually on the trunk, is accompanied by intense pruritus, and is usually unresponsive to topical corticosteroid therapy. Late rash may take weeks to disappear after penicillamine is stopped and usually recurs if the drug is restarted.

The appearance of a drug eruption accompanied by fever, arthralgia, lymphadenopathy or other allergic manifestations usually requires discontinuation of penicillamine.

Certain patients will develop a positive antinuclear antibody (ANA) test and some of these may show a lupus erythematosus-like syndrome similar to drug-induced lupus associated with other drugs. The lupus erythematosus-like syndrome is not associated with hypocomplementemia and may be present without nephropathy. The development of a positive ANA test does not mandate discontinuance of the drug; however, the physician should be alerted to the possibility that a lupus erythematosus-like syndrome may develop in the future.

Some patients may develop oral ulcerations which in some cases have the appearance of aphthous stomatitis. The stomatitis usually recurs on rechallenge but often clears on a lower dosage. Although rare, cheilosis, glossitis and gingivostomatitis have also been reported. These oral lesions are frequently dose-related and may preclude further increase in penicillamine dosage or require discontinuation of the drug.

Hypogeusia (a blunting or diminution in taste perception) has occurred in some patients. This may last two to three months or more and may develop into a total loss of taste; however, it is usually self-limited despite continued penicillamine treatment. Such taste impairment is rare in patients with Wilson's disease.

Penicillamine should not be used in patients who are receiving concurrently gold therapy, antimalarial or cytotoxic drugs, oxyphenbutazone or phenylbutazone because these drugs are also associated with similar serious hematologic and renal adverse reactions.

Patients who have had gold salt therapy discontinued due to a major toxic reaction may be at greater risk of serious adverse reactions with penicillamine but not necessarily of the same type.

Patients who are allergic to penicillin may theoretically have cross-sensitivity to penicillamine. The possibility of reactions from contamination of penicillamine by trace amounts of penicillin has been eliminated now that penicillamine is being produced synthetically rather than as a degradation product of penicillin.

Patients with Wilson's disease or cystinuria should be given 25 mg/day of pyridoxine during therapy, since penicillamine increases the requirement for this vitamin. Patients also may receive benefit from a multivitamin preparation, although there is no evidence that deficiency of any vitamin other than pyridoxine is associated with penicillamine. In Wilson's disease, multivitamin preparations must be copper-free.

Rheumatoid arthritis patients whose nutrition is impaired should also be given a daily supplement of pyridoxine. Mineral supplements should not be given, since they may block the response to penicillamine. Iron deficiency may develop, especially in pediatric patients and in menstruating women. In Wilson's disease, this may be a result of adding the effects of the low copper diet, which is probably also low in iron, and the penicillamine to the effects of blood loss or growth. In cystinuria, a low methionine diet may contribute to iron deficiency, since it is necessarily low in protein. If necessary, iron may be given in short courses, but a period of two hours should elapse between administration of penicillamine and iron, since orally administered iron has been shown to reduce the effects of penicillamine.

Penicillamine causes an increase in the amount of soluble collagen. In the rat this results in inhibition of normal healing and also a decrease in tensile strength of intact skin. In man this may be the cause of increased skin friability at sites especially subject to pressure or trauma, such as shoulders, elbows, knees, toes, and buttocks. Extravasations of blood may occur and may appear as purpuric areas, with external bleeding if the skin is broken, or as vesicles containing dark blood. Neither type is progressive. There is no apparent association with bleeding elsewhere in the body and no associated coagulation defect has been found. Therapy with penicillamine may be continued in the presence of these lesions. They may not recur if dosage is reduced. Other reported effects probably due to the action of penicillamine on collagen are excessive wrinkling of the skin and development of small, white papules at venipuncture and surgical sites.

The effects of penicillamine on collagen and elastin make it advisable to consider a reduction in dosage to 250 mg/day, when surgery is contemplated. Reinstitution of full therapy should be delayed until wound healing is complete.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal carcinogenicity studies have not been done with penicillamine. There is a report that five of ten autoimmune disease-prone NZB hybrid mice developed lymphocytic leukemia after 6 months' intraperitoneal treatment with a dose of 400 mg/kg penicillamine 5 days per week.

Penicillamine is directly mutagenic to S. typhimurium strain TA92 in the Ames test; mutagenicity is enhanced by kidney postmitochondrial subcellular fraction 9. Penicillamine does not induce gene mutations in Chinese hamster V79 cells.

Penicillamine induces sister-chromatid exchanges and chromosome aberrations in cultivated mammalian cells. No studies on the effect of penicillamine on fertility are available.

Pregnancy

Pregnancy Category D

(see WARNINGS, Pregnancy)

Nursing Mothers

See CONTRAINDICATIONS.

Pediatric Use

The efficacy of CUPRIMINE (penicillamine) in juvenile rheumatoid arthritis has not been established.

Geriatric Use

Clinical studies of CUPRIMINE (penicillamine) are limited in subjects aged 65 and over; they did not include sufficient numbers of elderly subjects aged 65 and over to adequately determine whether they respond differently from younger subjects. Review of reported clinical trials with penicillamine in the elderly suggest greater risk than in younger patients for overall skin rash and abnormality of taste. In general, dose selection for an elderly patient should be cautious, starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drugs.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and careful monitoring of renal function is recommended.

REFERENCES

*** Scheinberg, I.H.; Sternlieb, I.: N. Engl. J. Med. 293: 1300-1302, Dec. 18, 1975.

Last reviewed on RxList: 12/17/2008
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

No information provided.

CONTRAINDICATIONS

Except for the treatment of Wilson's disease or certain patients with cystinuria, use of penicillamine during pregnancy is contraindicated (see WARNINGS).

Although breast milk studies have not been reported in animals or humans, mothers on therapy with penicillamine should not nurse their infants.

Patients with a history of penicillamine-related aplastic anemia or agranulocytosis should not be restarted on penicillamine (see WARNINGS and ADVERSE REACTIONS).

Because of its potential for causing renal damage, penicillamine should not be administered to rheumatoid arthritis patients with a history or other evidence of renal insufficiency.

Last reviewed on RxList: 12/17/2008
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Penicillamine is a chelating agent recommended for the removal of excess copper in patients with Wilson's disease. From in vitro studies which indicate that one atom of copper combines with two molecules of penicillamine, it would appear that one gram of penicillamine should be followed by the excretion of about 200 milligrams of copper; however, the actual amount excreted is about one percent of this.

Penicillamine also reduces excess cystine excretion in cystinuria. This is done, at least in part, by disulfide interchange between penicillamine and cystine, resulting in formation of penicillamine-cysteine disulfide, a substance that is much more soluble than cystine and is excreted readily.

Penicillamine interferes with the formation of cross-links between tropocollagen molecules and cleaves them when newly formed.

The mechanism of action of penicillamine in rheumatoid arthritis is unknown although it appears to suppress disease activity. Unlike cytotoxic immunosuppressants, penicillamine markedly lowers IgM rheumatoid factor but produces no significant depression in absolute levels of serum immunoglobulins. Also unlike cytotoxic immunosuppressants which act on both, penicillamine in vitro depresses T-cell activity but not B-cell activity.

In vitro, penicillamine dissociates macroglobulins (rheumatoid factor) although the relationship of the activity to its effect in rheumatoid arthritis is not known.

In rheumatoid arthritis, the onset of therapeutic response to CUPRIMINE (penicillamine) may not be seen for two or three months. In those patients who respond, however, the first evidence of suppression of symptoms such as pain, tenderness, and swelling is generally apparent within three months. The optimum duration of therapy has not been determined. If remissions occur, they may last from months to years, but usually require continued treatment (see DOSAGE AND ADMINISTRATION).

In all patients receiving penicillamine, it is important that CUPRIMINE (penicillamine) be given on an empty stomach, at least one hour before meals or two hours after meals, and at least one hour apart from any other drug, food, milk, antacid, zinc or iron-containing preparation. This permits maximum absorption and reduces the likelihood of inactivation by metal binding in the gastrointestinal tract.

Pharmacokinetics

Penicillamine is absorbed rapidly but incompletely (40-70%) from the gastrointestinal tract, with wide interindividual variations. Food, antacids, and iron reduce absorption of the drug. The peak plasma concentration of penicillamine occurs 1-3 hours after ingestion; it is approximately 1-2 mg/L after an oral dose of 250 mg. The drug appears in the plasma as free penicillamine, penicillamine disulfide, and cysteine-penicillamine disulfide. When prolonged treatment is stopped, there is a slow elimination phase lasting 4-6 days.

More than 80% of plasma penicillamine is bound to proteins, especially albumin and ceruloplasmin. The drug also binds to erythrocytes and macrophages. A small fraction of the dose is metabolized in the liver to S-methyl-D-penicillamine. Excretion is mainly renal, mainly as disulfides.

Last reviewed on RxList: 12/17/2008
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

Last reviewed on RxList: 12/17/2008
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

Last reviewed on RxList: 12/17/2008
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Cuprimine Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

PENICILLAMINE - ORAL

(PEN-i-SIL-a-meen)

COMMON BRAND NAME(S): Cuprimine, Depen

USES: This medication is used to treat rheumatoid arthritis, Wilson's disease (a condition in which high levels of copper in the body cause damage to the liver, brain, and other organs), and a certain disorder which causes kidney stones (cystinuria). For the treatment of rheumatoid arthritis, penicillamine is known as a disease-modifying antirheumatic drug (DMARD). It helps to decrease pain/tenderness/swelling in the joints. For the treatment of Wilson's disease, penicillamine binds to copper and helps it to be removed from the body. Decreasing copper levels helps to improve liver function and the mental/mood/nerve problems (such as confusion, difficulty speaking/walking) caused by the disease. For the treatment of cystinuria, penicillamine helps to decrease the amount of a certain substance (cystine) in the urine which can cause kidney stones.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This drug may also be used to treat lead poisoning.

HOW TO USE: Take this medication by mouth on an empty stomach (1 hour before or 2 hours after meals) as directed by your doctor. Take this medication at least 1 hour apart from other drugs (especially antacids), milk, or food.

Dosage is based on your medical condition and response to treatment.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same time(s) each day.

Your doctor may also direct you to take vitamin B6 (pyridoxine) and iron. Follow your doctor's instructions carefully. If you need to take iron or other products that contain minerals (such as zinc), take it at least 2 hours before or after taking penicillamine. Consult your doctor before taking any products containing minerals since they may block the absorption of penicillamine.

For the treatment of rheumatoid arthritis, it may take 2 to 3 months before you see any improvement in your condition.

For the treatment of Wilson's disease, follow the diet recommended by your doctor to get the most benefit from this medication. Your condition may not improve for 1 to 3 months and may actually get worse when you start this medication. Tell your doctor immediately if your condition continues to worsen after a month of treatment.

For the treatment of cystinuria, follow the diet recommended by your doctor to get the most benefit from this medication. Drink plenty of water unless your doctor directs you otherwise.

Tell your doctor if your condition does not improve or if it worsens.

Disclaimer

Cuprimine Consumer (continued)

SIDE EFFECTS: Stomach/abdominal pain, nausea/vomiting, loss of appetite, diarrhea, and decreased sense of taste may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: signs of infection (such as fever, persistent sore throat, swollen lymph nodes), easy bruising/bleeding, unusual tiredness, rapid breathing, skin blisters, mouth sores, new or worsening joint pain, thinning/wrinkling skin.

Tell your doctor immediately if any of these rare but serious side effects occur: change in the amount of urine, bloody urine, coughing up blood, shortness of breath, muscle weakness, eye problems (such as drooping eyelids, blurred vision), persistent nausea/vomiting, severe stomach/abdominal pain, dark urine, yellowing eyes/skin.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Cuprimine (penicillamine) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before taking penicillamine, tell your doctor or pharmacist if you are allergic to it; or to penicillins; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: a previous severe reaction to penicillamine (such as aplastic anemia, agranulocytosis), kidney disease, blood/bone marrow disorders (such as thrombocytopenia).

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

Penicillamine is not recommended for use during pregnancy. It may harm an unborn baby. However, it may sometimes be used during pregnancy in certain situations (such as treating Wilson's disease). Consult your doctor for more details.

It is unknown if this medication passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

Disclaimer

Cuprimine Consumer (continued)

DRUG INTERACTIONS: See also How to Use section.

The effects of some drugs can change if you take other drugs or herbal products at the same time. This can increase your risk for serious side effects or may cause your medications not to work correctly. These drug interactions are possible, but do not always occur. Your doctor or pharmacist can often prevent or manage interactions by changing how you use your medications or by close monitoring.

To help your doctor and pharmacist give you the best care, be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products) before starting treatment with this product. While using this product, do not start, stop, or change the dosage of any other medicines you are using without your doctor's approval.

Some products that may interact with this drug include: digoxin, gold salts (such as auranofin), drugs to treat malaria (such as chloroquine), phenylbutazone, other drugs that decrease bone marrow function (such as azathioprine, cancer chemotherapy, trimethoprim/sulfamethoxazole).

This document does not contain all possible drug interactions. Keep a list of all the products you use. Share this list with your doctor and pharmacist to lessen your risk for serious medication problems.

OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (such as complete blood count, hematocrit/hemoglobin, liver function, urine test, physical exam) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised May 2010. Copyright(c) 2010 First Databank, Inc.

Cuprimine Patient Information Including Side Effects

Brand Names: Cuprimine, Depen

Generic Name: penicillamine (Pronunciation: pen ih SILL ah meen)

What is penicillamine (Cuprimine)?

Penicillamine is a chelating agent. It attaches to other chemicals in the body, which aids in their removal.

Penicillamine is used to remove excess copper associated with Wilson's disease. It is also used to reduce cystine in the urine and to treat severe rheumatoid arthritis.

Penicillamine may also be used for purposes other than those listed in this medication guide.

Depen 250 mg

oval, white, imprinted with 37 4401, WALLACE

What are the possible side effects of penicillamine (Cuprimine)?

If you experience any of the following serious side effects, seek emergency medical attention or contact your doctor immediately:

  • an allergic reaction (shortness of breath; closing of your throat; difficulty breathing; swelling of your lips, face, or tongue; or hives);
  • fever or chills;
  • a sore throat;
  • unusual bleeding or bruising;
  • blood in the urine;
  • unexplained shortness of breath, coughing, or wheezing;
  • abdominal pain;
  • yellow skin or eyes;
  • muscle weakness; or
  • double vision.

Other, less serious side effects may be more likely to occur. Continue to take penicillamine and notify your doctor if you experience

  • itching or a rash;
  • nausea, vomiting, diarrhea, or decreased appetite;
  • ringing in the ears;
  • decreased taste;
  • sores in the mouth;
  • poor wound healing; or
  • increased wrinkling of the skin.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

Read the Cuprimine (penicillamine) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about penicillamine (Cuprimine)?

Notify your doctor immediately if you develop fever; chills; a sore throat; unusual bruising or bleeding; blood in your urine, unexplained shortness of breath, coughing, or wheezing; muscle weakness; or double vision. These symptoms could be early signs of dangerous side effects.

Side Effects Centers

Cuprimine Patient Information including How Should I Take

What should I discuss with my healthcare provider before taking penicillamine (Cuprimine)?

You cannot take penicillamine if you have taken it in the past and it has damaged your blood cells.

Before taking penicillamine, tell your doctor if you have kidney disease or any other serious illness. You may not be able to take penicillamine, or you may require a lower dose or special monitoring during therapy.

Penicillamine may cause birth defects in an unborn baby. However, it has also been used during pregnancy with no evidence of defects. Penicillamine should not be used during pregnancy except to treat Wilson's disease and some cases of cystine in the urine. Do not take this medication without first talking to your doctor if you are pregnant.

It is not known whether penicillamine passes into breast milk. Since penicillamine may harm a nursing infant, breast-feeding is not recommended during treatment with this medication.

How should I take penicillamine (Cuprimine)?

Take penicillamine exactly as directed by your doctor. If you do not understand these instructions, ask your pharmacist, nurse, or doctor to explain them to you.

Take each dose with a full glass of water.

Penicillamine must be taken on an empty stomach, at least 1 hour before or 2 hours after a full meal, and at least 1 hour before or after any other drug, food, or milk. Taking penicillamine with anything else in the stomach greatly decreases its effectiveness.

Do not stop taking penicillamine without first talking to your doctor. Stopping therapy may cause your body to react abnormally when therapy is restarted. If you do stop taking the medication, do not restart without first talking to your doctor. You may need special monitoring.

Your doctor may want you to take a vitamin and mineral supplement during treatment with penicillamine. Penicillamine may reduce vitamin B6 and iron in the body. Follow your doctor's instructions.

Store penicillamine at room temperature away from moisture and heat.

Side Effects Centers

Cuprimine Patient Information including If I Miss a Dose

What happens if I miss a dose (Cuprimine)?

Take the missed dose on an empty stomach as soon as you remember. However, if it is almost time for your next dose, skip the dose you missed and take only your next regularly scheduled dose. Do not take a double dose of this medication unless otherwise directed by your doctor. If you have missed several doses in a row, do not take any more doses without first talking to your doctor.

What happens if I overdose (Cuprimine)?

Seek emergency medical attention.

Symptoms of a penicillamine overdose are not known.

What should I avoid while taking penicillamine (Cuprimine)?

Follow any special diet restrictions recommended by your doctor.

What other drugs will affect penicillamine (Cuprimine)?

Do not take penicillamine if you are taking any of the following medicines:

  • a gold-therapy product such as auranofin (Ridaura), aurothioglucose (Solganal), or gold sodium thiomalate (Myochrysine, Aurolate);
  • an antimalarial medicine such as quinine (Quinamm), mefloquine (Lariam), chloroquine (Aralen), hydroxychloroquine (Plaquenil), primaquine, or pyrimethamine (Daraprim);
  • a cancer chemotherapy medicine; or
  • phenylbutazone.

Like penicillamine, the medications listed above can affect the blood and the kidneys. Combined with penicillamine, any of these medicines can be very dangerous.

Before taking penicillamine, tell your doctor if you are taking digoxin (Lanoxin, Lanoxicaps). Penicillamine may decrease the effects of digoxin, and your doctor may want to adjust your dosage or monitor your therapy.

Many other drugs, especially antacids and vitamin and mineral supplements, can decrease the effects of penicillamine. Do not take any medicines or over-the-counter drugs or supplements within 1 hour of a penicillamine dose.

Drugs other than those listed here may also interact with penicillamine. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines.

Where can I get more information?

Your pharmacist has additional information about penicillamine written for health professionals that you may read.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 2.03. Revision date: 12/15/2010.

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