Distamine 250mg Film-coated tablets.

Penicillamine 250mg Film-coated tablets

Each tablet contains 250mg D-penicillamine.

For excipients see section 6.1

Film-coated Tablet.

White, film-coated tablet with a diameter of 10mm, marked “DM” on one face and “250” on the other.

a) Severe active rheumatoid arthritis, including juvenile forms

b) Wilson's disease (hepatolenticular degeneration)

c) Cystinuria – dissolution and prevention of cystine stones

d) Lead poisoning

e) Chronic active hepatitis

For oral administration.

Distamine should be taken on an empty stomach at least half an hour before meals, or on retiring.

a) Rheumatoid arthritis

Adults: 125 to 250mg daily for the first month. Increase by the same amount every four to 12 weeks until remission occurs. The minimum maintenance dose to achieve suppression of symptoms should be used and treatment should be discontinued if no benefit is obtained within 12 months. Improvement may not occur for some months.

The usual maintenance dose is 500 to 750mg daily. Up to 1500mg daily may be required.

If remission is established and has been sustained for six months, gradual reduction by 125 to 250mg amounts every 12 weeks may be attempted.

The elderly: Initial dose should not exceed 125mg daily for the first month, increasing by similar increments every four to 12 weeks until the minimum maintenance dose to suppress symptoms is reached. Daily dosage should not exceed 1000mg (see Section 4.4, “Special Warnings and Precautions for Use”).

Children: The usual maintenance dose is 15 to 20mg/kg/day. The initial dose should be lower (2.5 to 5mg/kg/day) and increased every four weeks over a period of three to six months. Please note that as the smallest available tablet is 125mg, this may not be suitable for children under eight years (or less than 26kg in weight).

Renal insufficiency: Distamine therapy should be initiated at a low dose with intervals between dose increase of at least twelve weeks. Fortnightly monitoring for toxicity is mandatory throughout treatment for rheumatoid arthritis.

b) Wilson's disease

Patients must be maintained in negative copper balance and the minimum dose of Distamine required to achieve this should be given.

Adults: 1500 to 2000mg daily in divided doses. Dose may be reduced to 750 to 1000mg daily when control of the disease is achieved. It is advisable that a dose of 2000mg/day should not be continued for more than a year.

The elderly: 20mg/kg/day in divided doses adjusting the dose to minimal level necessary to control disease.

Children: Up to 20mg/kg/day in divided doses. Minimum dose 500mg/day.

Renal insufficiency: Extra precautions should be taken to monitor for adverse effects in patients with Wilson's disease and renal insufficiency.

c) Cystinuria

Ideally, establish the lowest effective dose by quantitative amino acid chromatography of urine.

(i) Dissolution of cystine stones:

Adults: 1000 to 3000mg daily in divided doses.

Urine cystine levels of not more than 200mg/l should be maintained.

(ii) Prevention of cystine stones:

Adults: 500 to 1000mg on retiring. Fluid intake should be not less than 3 litres/day. Urine cystine levels of not more than 300mg/l should be maintained.

The elderly: Use the minimum dose to maintain urinary cystine levels below 200mg/l.

Children: No dose range established, but urinary cystine levels must be kept below 200mg/l. The minimum dose of Distamine required to achieve this should be given.

Renal insufficiency: If renal insufficiency is present at the onset of therapy, the starting dose should be lower, but it will be necessary to give sufficient Distamine to achieve urine cystine levels of not more than 300mg/l. The maintenance dose should be reviewed at intervals of not more than four weeks.

d) Lead poisoning

Adults: 1000 to 1500mg daily in divided doses until urinary lead is stabilised at less than 0.5mg/day.

The elderly: 20mg/kg/day in divided doses until urinary lead is stabilised at less than 0.5mg/day.

Children: 20mg/kg/day.

e) Chronic active hepatitis

Adults: For maintenance treatment after the disease process has been brought under control with corticosteroids. The initial dose of 500mg daily, in divided doses, should be increased gradually over three months to a maintenance dose of 1250mg daily. During this period, the dose of corticosteroids should be phased out. Throughout therapy, liver function tests should be carried out periodically to assess the disease status.

The elderly: Not recommended.

Hypersensitivity to penicillamine or any of the ingredients.

Agranulocytosis or severe thrombocytopenia due to penicillamine.

Lupus erythematosus.

Moderate or severe renal impairment.

Full blood and platelet counts should be performed and renal function should be assessed prior to treatment with penicillamine.

During the first eight weeks of therapy full blood counts should be carried out weekly or fortnightly and also in the week after any increase in dose, otherwise monthly thereafter. In cystinuria or Wilson's disease, longer intervals may be adequate.

Withdrawal of treatment should be considered if platelets fall below 120,000/mm³ or white blood cells below 2,500/mm³, or if three successive falls are noted within the normal range. Treatment may be restarted at a reduced dose when counts return to normal, but should be permanently withdrawn on recurrence of leucopenia or thrombocytopenia.

In patients with normal renal function, urinalysis for detection of haematuria and proteinuria should be carried out weekly at first, and following each increase in dose, then monthly, although longer intervals may be adequate for cystinuria and Wilson's disease. Increasing or persistent proteinuria may necessitate withdrawal of therapy.

Care should be exercised in patients with renal insufficiency; modification of dosage may be necessary (see Section 4.2, “Posology and Method of Administration”).

Especially careful monitoring is necessary in the elderly since increased toxicity has been observed in this patient population regardless of renal function.

Concomitant use of NSAIDs and other nephrotoxic drugs may increase the risk of renal damage.

Penicillamine should be used with caution in patients who have had adverse reactions to gold.

Concomitant or previous treatment with gold may increase the risk of side effects with penicillamine treatment. Therefore penicillamine should be used with caution in patients who have previously had adverse reactions to gold and concomitant treatment with gold should be avoided.

If concomitant oral iron therapy is indicated, this should not be given within two hours of taking penicillamine.

Antihistamines, steroid cover, or temporary reduction of dose will control urticarial reactions.

Reversible loss of taste may occur. Mineral supplements to overcome this are not recommended.

Haematuria is rare, but if it occurs in the absence of renal stones or other known cause, treatment should be stopped immediately.

A late rash, described as acquired epidermolysis bullosa and penicillamine dermopathy, may occur after several months or years of therapy. This may necessitate a reduction in dosage.

Breast enlargement has been reported as a rare complication of penicillamine therapy in both women and men. Danazol has been used successfully to treat breast enlargement which does not regress on drug discontinuation.

Concomitant iron and penicillamine treatment: oral absorption of penicillamine may be reduced by concomitant administration of iron (see Section 4.4 “Special Warnings and Precautions for Use”).

Concomitant use of NSAIDs and other nephrotoxic drugs may increase the risk of renal damage (see Section 4.4 “Special Warnings and Precautions for Use”).

Concomitant gold and penicillamine treatment: concomitant use not recommended (see Section 4.4 “Special Warnings and Precautions for Use”).

Usage in pregnancy: The safety of penicillamine for use during pregnancy has not been established (see Section 5.3, “Preclinical Safety Data”).

Wilson's disease: There have been several cases of reversible cutis laxa in infants born to mothers taking penicillamine throughout pregnancy. Although there have been no controlled studies on the use of penicillamine during pregnancy, two retrospective studies have reported the successful delivery of 43 normal infants to 28 women receiving between 500 and 2000mg of penicillamine daily. There are also anecdotal reports both of congenital abnormalities and of successful outcomes in patients who have remained on penicillamine during pregnancy. If treatment with penicillamine is to be continued following a risk-benefit analysis, consideration should be given to reducing the dose of penicillamine to the lowest effective dose.

Cystinuria: Whilst normal infants have been delivered, there is one report of a severe connective tissue abnormality in the infant of a mother who received 2000mg penicillamine daily throughout pregnancy. Whenever possible, penicillamine should be withheld during pregnancy, but if stones continue to form, the benefit of resuming treatment must be weighed against the possible risk to the foetus.

Rheumatoid arthritis or chronic active hepatitis: Penicillamine should not be administered to patients who are pregnant, and therapy should be stopped when pregnancy is diagnosed or suspected, unless considered to be absolutely essential by the physician.

Usage in lactation: Due to the lack of data on use in breast feeding patients and the possibility that penicillamine may be transmitted to newborns through breast milk, Distamine should only be used in breast feeding patients when it is considered absolutely essential by the physician.

None known.

NB: The incidence and severity of some of the adverse reactions, noted below, varies according to the dosage and nature of the disease under treatment.

Nausea, anorexia, fever and rash may occur early in therapy, especially when full doses are given from the start.

Urticarial reactions have been reported (see Section 4.4, “Special Warnings and Precautions for Use”).

Reversible loss of taste may occur (see Section 4.4, “Special Warnings and Precautions for Use”).

Rarely, mouth ulceration/stomatitis has occurred.

Thrombocytopenia occurs commonly and leucopenia less often. These reactions may occur at any time during treatment and are usually reversible (see Section 4.4, “Special Warnings and Precautions for Use”).

Deaths from agranulocytosis and aplastic anaemia have occurred.

Deterioration of the neurological symptoms of Wilson's disease (dystonia, rigidity, tremor, dysarthria) have been reported following introduction of penicillamine in patients treated for this condition. This may be a consequence of mobilisation and redistribution of copper from the liver to the brain.

Proteinuria occurs in up to 30% of patients and is partially dose-related (see Section 4.4, “Special Warnings and Precautions for Use”).

Haematuria may occur rarely (see Section 4.4, “Special Warnings and Precautions for Use”).

Other rare adverse reactions are as follows: alopecia and inflammatory conditions of the respiratory system, such as bronchiolitis and pneumonitis.

Other complications have included haemolytic anaemia, nephrotic syndrome, glomerulonephritis, pulmonary haemorrhage, Goodpasture's syndrome, pancreatitis, cholestatic jaundice (including raised liver function tests), drug induced lupus erythematosus, and conditions closely resembling myasthenia gravis, polymyositis (with rare cardiac involvement), dermatomyositis, pemphigus, Stevens-Johnson syndrome and rheumatoid arthritis.

A late rash, described as acquired epidermolysis bullosa and penicillamine dermopathy, may occur after several months or years of therapy (see Section 4.4, “Special Warnings and Precautions for Use”).

Pseudoxanthoma elasticum, elastosis perforans and skin laxity have been reported rarely. Breast enlargement has been reported as a rare complication of penicillamine therapy in both women and men. In some patients breast enlargement was considerable and/or prolonged with poor resolution and others required surgery (see Section 4.4, “Special Warnings and Precautions for Use”).

The use of DMARDs, including penicillamine, has been linked to the development of septic arthritis in patients with rheumatoid arthritis, although rheumatoid arthritis is a stronger predictor for the development of septic arthritis than the use of a DMARD.

No instances of adverse reactions to an overdose of penicillamine have been recorded and no specific measures are indicated.

Pharmacotherapeutic group: M01C C

1. Penicillamine is used to treat severe active rheumatoid arthritis not adequately controlled by NSAID therapy.

2. Penicillamine is a chelating agent which aids the elimination from the body of certain heavy metal ions, including copper, lead and mercury, by forming stable soluble complexes with them that are readily excreted by the kidney.

3. It is used in the treatment of Wilson's disease (hepatolenticular degeneration), in conjunction with a low copper diet, to promote the excretion of copper.

4. It may be used to treat asymptomatic lead intoxication.

5. Penicillamine is used as an adjunct to diet and urinary alkalinisation in the management of cystinuria. By reducing urinary concentrations of cystine, penicillamine prevents the formation of calculi and promotes the gradual dissolution of existing calculi.

6. Desensitisation. Should the physician deem it necessary to attempt to desensitise a patient to penicillamine, it should be noted that this formulation is not suitable for this purpose.

Penicillamine is a thiol-group containing chelating agent, variably absorbed from the gastrointestinal tract. The drug undergoes a rapid distribution phase, followed by a slower elimination phase.

Penicillamine is strongly plasma-protein bound. Most penicillamine is bound to albumin but some is bound to α-globulins or ceruloplasmin.

Penicillamine is not extensively metabolised in man.

About 80% of the absorbed dose is excreted rapidly in the urine, mostly as mixed disulphides. Some of the dose is excreted as a penicillamine copper complex and some as the S-methyl derivative.

Penicillamine has been shown to be teratogenic in rats when given in doses several times higher than those recommended for human use.

There is no known LD50 value for penicillamine. In studies some rats died after oral administration of 10,000mg/kg, but intra-peritoneal injections of a dose of 660mg/kg caused no deaths.

Tablet Core

Microcrystalline cellulose

Sodium starch glycolate (Type A)

Povidone

Magnesium stearate

Tablet Coating

Glycerol

Titanium dioxide (E171)

Hypromellose

Not applicable.

3 years

Do not store above 25°C. Keep the bottle tightly closed.

HDPE bottle with screw cap, containing 100 tablets.

No special requirements.

Alliance Pharmaceuticals Ltd

Avonbridge House

Bath Road

Chippenham

Wiltshire

SN15 2BB

United Kingdom

PL 16853/0058

12^th October 2005

27th March 2009