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Opção de tratamento:
Medicamente revisado por Fedorchenko Olga Valeryevna, Farmácia Última atualização em 07.04.2022
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A Kelatina é indicada no tratamento da doença de Wilson, cistinúria e em pacientes com artrite reumatóide ativa e grave que não responderam a um estudo adequado de terapia convencional. As evidências disponíveis sugerem que a Kelatina não tem valor na espondilite anquilosante.
Doença de Wilson
A doença de Wilson (degeneração hepatolenticular) ocorre em indivíduos que herdaram um defeito autossômico recessivo que leva a um acúmulo de cobre muito além dos requisitos metabólicos. O excesso de cobre é depositado em vários órgãos e tecidos e, eventualmente, produz efeitos patológicos principalmente no fígado, onde os danos progridem para a cirrose pós-necrótica e no cérebro, onde a degeneração é generalizada. O cobre também é depositado como anéis característicos, assintomáticos, dourados, Kayser-Fleischer nas córneas de todos os pacientes com sintomatologia cerebral e de alguns pacientes assintomáticos ou que manifestam apenas sintomatologia hepática.
Dois tipos de pacientes necessitam de tratamento para a doença de Wilson: (1) o sintomático e (2) o assintomático em quem se pode presumir que a doença se desenvolverá no futuro se o paciente não for tratado.
O diagnóstico, se houver suspeita com base na história familiar ou individual ou no exame físico, pode ser confirmado se a ceruloplasmina plasmática de proteína de cobre ** for <20 mg / dL e uma determinação quantitativa em uma amostra de biópsia hepática mostrar uma concentração anormalmente alta de cobre ( > 250 mcg / g de peso seco) ou anéis Kayser-Fleischer estão presentes.
O tratamento tem dois objetivos:
- minimizar a ingestão alimentar de cobre;
- promover excreção e formação complexa (ou seja,., desintoxicação) do excesso de cobre nos tecidos.
O primeiro objetivo é alcançado por uma dieta diária que contém não mais que um ou dois miligramas de cobre. Essa dieta deve excluir, mais importante, chocolate, nozes, frutos do mar, cogumelos, fígado, melaço, brócolis e cereais e suplementos alimentares enriquecidos com cobre, e ser composta na maior extensão possível de alimentos com baixo teor de cobre. Água destilada ou desmineralizada deve ser usada se a água potável do paciente contiver mais de 0,1 mg de cobre por litro.
Para o segundo objetivo, é utilizado um agente quelante de cobre.
Em pacientes sintomáticos, esse tratamento geralmente produz melhora neurológica acentuada, desbotamento dos anéis Kayser-Fleischer e melhora gradual da disfunção hepática e distúrbios psíquicos.
A experiência clínica até o momento sugere que a vida é prolongada com o regime acima.
Melhoria perceptível pode não ocorrer por um a três meses. Ocasionalmente, os sintomas neurológicos pioram durante o início da terapia com Kelatine. Apesar disso, o medicamento não deve ser retirado. A interrupção temporária acarreta um risco aumentado de desenvolver uma reação de sensibilidade após a retomada da terapia, embora possa resultar em melhora clínica dos sintomas neurológicos (ver AVISO). Se os sintomas e sinais neurológicos continuarem a piorar por um mês após o início da terapia com Kelatine, podem ser considerados vários cursos curtos de tratamento com 2,3 - dimercaprol (BAL) enquanto a Kelatina continua.
O tratamento de pacientes assintomáticos é realizado há mais de trinta anos. Sintomas e sinais da doença parecem ser evitados indefinidamente se o tratamento diário com Kelatine for continuado.
Cistinúria
A cistinúria é caracterizada pela excreção urinária excessiva dos aminoácidos dibásicos, arginina, lisina, ornitina e cistina e o dissulfeto misto de cisteína e homocisteína. O defeito metabólico que leva à cistinúria é herdado como uma característica autossômica e recessiva. O metabolismo dos aminoácidos afetados é influenciado por pelo menos dois fatores anormais: (1) absorção gastrointestinal defeituosa e (2) disfunção tubular renal.
Arginina, lisina, ornitina e cisteína são substâncias solúveis, prontamente excretadas. Não há patologia aparente relacionada à sua excreção em quantidades excessivas.
A cistina, no entanto, é tão levemente solúvel na faixa usual de pH urinário que não é excretada prontamente e, portanto, cristaliza e forma pedras no trato urinário. A formação de pedra é a única patologia conhecida na cistinúria.
A produção diária normal de cistina é de 40 a 80 mg. Na cistinúria, a produção é bastante aumentada e pode exceder 1 g / dia. De 500 a 600 mg / dia, a formação de pedra é quase certa. Quando é superior a 300 mg / dia, o tratamento é indicado.
O tratamento convencional é direcionado para manter a cistina urinária diluída o suficiente para impedir a formação de pedras, mantendo a urina alcalina o suficiente para dissolver o máximo possível de cistina e minimizando a produção de cistina por uma dieta pobre em metionina (o principal precursor alimentar da cistina). Os pacientes devem beber líquido suficiente para manter a gravidade específica da urina abaixo de 1.010, tomar alcalino suficiente para manter o pH urinário entre 7,5 e 8 e manter uma dieta pobre em metionina. Esta dieta não é recomendada em crianças em crescimento e provavelmente é contra-indicada na gravidez devido ao seu baixo teor de proteínas (ver PRECAUÇÕES).
Quando essas medidas são inadequadas para controlar a formação recorrente de pedras, Kelatine pode ser usado como terapia adicional e, quando os pacientes se recusam a aderir ao tratamento convencional, Kelatine pode ser um substituto útil. É capaz de manter a excreção de cistina em valores quase normais, dificultando a formação de pedras e as sérias conseqüências da pielonefrite e da função renal comprometida que se desenvolvem em alguns pacientes.
Bartter e colegas descrevem o processo pelo qual a penicilamina interage com a cistina para formar dissulfeto misto de penicilamina-cisteína como :
CSSC = cistina
CS '= cisteína desprotonada
PSSP = dissulfeto de penicilamina
PS '= penicilamina sulfidril desprotonada
CSSP = dissulfeto misto de penicilamina-cisteína
Nesse processo, supõe-se que a forma desprotonada de penicilamina, PS ', seja o fator ativo para promover o intercâmbio de dissulfetos.
Artrite reumatóide
Como a Kelatina pode causar reações adversas graves, seu uso na artrite reumatóide deve ser restrito a pacientes com doença grave e ativa e que não responderam a um estudo adequado da terapia convencional. Mesmo assim, a relação benefício / risco deve ser cuidadosamente considerada. Outras medidas, como repouso, fisioterapia, salicilatos e corticosteróides, devem ser usadas, quando indicado, em conjunto com Kelatine (ver PRECAUÇÕES).
In all patients receiving penicillamine, it is important that Kelatine 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 Kelatine.
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 Kelatine, 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 Kelatine 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 Kelatine 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 Kelatine, 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 Kelatine.
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 Kelatine 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 Kelatine 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 Kelatine should be discontinued.
Maintenance Therapy
The maintenance dosage of Kelatine 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 Kelatine 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 anti-inflammatory 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 Kelatine 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 Kelatine 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
Kelatine 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 Kelatine 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.
Exceto no tratamento da doença de Wilson ou de certos pacientes com cistinúria, o uso de penicilamina durante a gravidez é contra-indicado (ver AVISO).
Embora não tenham sido relatados estudos sobre o leite materno em animais ou humanos, as mães em terapia com penicilamina não devem amamentar seus bebês.
Pacientes com histórico de anemia aplástica ou agranulocitose relacionada à penicilamina não devem ser reiniciados com penicilamina (ver AVISO e REAÇÕES ADVERSAS).
Devido ao seu potencial de causar danos renais, a penicilamina não deve ser administrada a pacientes com artrite reumatóide com histórico ou outra evidência de insuficiência renal.
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 Kelatine (see ADVERSE REACTIONS). Occasionally, neurological symptoms become worse during initiation of therapy with Kelatine (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, Kelatine 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 Kelatine in juvenile rheumatoid arthritis has not been established.
Geriatric Use
Clinical studies of Kelatine 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. 8838-00
A penicilamina é um medicamento com alta incidência de reações indesejáveis, algumas das quais são potencialmente fatais. Portanto, é obrigatório que os pacientes que recebem terapia com penicilamina permaneçam sob rigorosa supervisão médica durante todo o período de administração do medicamento (ver AVISO e PRECAUÇÕES).
Incidências relatadas (%) para as reações adversas mais comuns em pacientes com artrite reumatóide são observadas, com base em 17 ensaios clínicos representativos relatados na literatura (1270 pacientes).
Alérgico
Prurido generalizado, erupções cutâneas precoces e tardias (5%), pênfigo (ver AVISO) e ocorreram erupções medicamentosas que podem ser acompanhadas por febre, artralgia ou linfadenopatia (ver AVISO e PRECAUÇÕES). Alguns pacientes podem apresentar uma síndrome do tipo lúpus eritematoso semelhante ao lúpus induzido por medicamentos produzido por outros agentes farmacológicos (ver PRECAUÇÕES).
Ocorreram urticária e dermatite esfoliativa.
Foi relatada tireoidite; foi relatada hipoglicemia em associação com anticorpos anti-insulina. Essas reações são extremamente raras.
Alguns pacientes podem desenvolver uma poliartralgia migratória, geralmente com sinovite objetiva (ver DOSAGEM E ADMINISTRAÇÃO).
Gastrointestinal
Anorexia, dor epigástrica, náusea, vômito ou diarréia ocasional podem ocorrer (17%).
Ocorreram casos isolados de úlcera péptica reativada, assim como disfunção hepática, incluindo insuficiência hepática e pancreatite. Colestase intra-hepática e hepatite tóxica foram relatadas raramente. Houve alguns relatos de aumento da fosfatase alcalina sérica, desidrogenase láctica e testes positivos de floculação e turbidez do timol por cefalina.
Alguns pacientes podem relatar uma contusão, diminuição ou perda total da percepção do paladar (12%); ou pode desenvolver ulcerações orais. Embora raros, foram relatados queilose, glossite e gengivostomatite (ver PRECAUÇÕES).
Os efeitos colaterais gastrointestinais são geralmente reversíveis após a interrupção da terapia.
Hematológico
A penicilamina pode causar depressão da medula óssea (ver AVISO). Leucopenia (2%) e trombocitopenia (4%) ocorreram. Foram relatadas fatalidades como resultado de trombocitopenia, agranulocitose, anemia aplástica e anemia sideroblástica.
Púrpura trombocitopênica trombótica, anemia hemolítica, aplasia de glóbulos vermelhos, monocitose, leucocitose, eosinofilia e trombocitose também foram relatadas.
Renal
Pacientes em terapia com penicilamina podem desenvolver proteinúria (6%) e / ou hematúria que, em alguns, podem progredir para o desenvolvimento da síndrome nefrótica como resultado de uma glomerulopatia membranosa do complexo imunológico (ver AVISO). Falha renal foi relatada.
Sistema nervoso central
Zumbido, neurite óptica e neuropatias sensoriais e motoras periféricas (incluindo poliradiculoneuropatia, ou seja,., Síndrome de Guillain-Barré) foram relatados. A fraqueza muscular pode ou não ocorrer com as neuropatias periféricas. Distúrbios visuais e psíquicos; transtornos mentais; e agitação e ansiedade foram relatadas.
Neuromuscular
Miastenia gravis (ver AVISO); distonia.
De outros
As reações adversas que foram relatadas raramente incluem tromboflebite; hiperpirexia (ver PRECAUÇÕES); queda de cabelo ou alopecia; líquen plano; polimiosite; dermatomiosite; hiperplasia mamária; elastose perfuranos serpiginosa; necrólise epidérmica tóxica; anetoderma (atrofia macular cutânea); e síndrome de Goodpasture, uma glomerulonefrite grave e finalmente fatal associada à hemorragia intra-alveolar AVISO). Vasculite, incluindo vasculite renal fatal, também foi relatada. Alveolite alérgica, bronquiolite obliterativa, pneumonite intersticial e fibrose pulmonar foram relatadas em pacientes com artrite reumatóide grave, alguns dos quais estavam recebendo penicilamina. Asma brônquica também foi relatada.
Foi relatada maior friabilidade da pele, rugas excessivas da pele e desenvolvimento de pequenas pápulas brancas na punção venosa e nos locais cirúrgicos (ver PRECAUÇÕES); síndrome das unhas amarelas.
A ação quelante da droga pode causar aumento da excreção de outros metais pesados, como zinco, mercúrio e chumbo.
Houve relatos associando penicilamina à leucemia. No entanto, as circunstâncias envolvidas nesses relatórios são tais que uma relação de causa e efeito com o medicamento não foi estabelecida.
Nenhuma informação fornecida.
However, we will provide data for each active ingredient