Penicillamine 250mg Tablets

1. Name of the medicinal product

Pendramine Tablets 250 mg

Penicillamine Tablets 250mg

 

2. Qualitative and quantitative composition

Each tablet contains 250mg D-penicillamine.

For excipients see section 6.1

 

3. Pharmaceutical form

Film-coated tablets.

White, biconvex, oblong, film-coated tablets, plain on one side, scored on the other side, containing 250mg D-penicillamine.

 

4. Clinical particulars

4.1 Therapeutic indications

a) Severe, active rheumatoid arthritis, including juvenile forms

b) Wilson's disease (hepatolenticular degeneration) in adults and children (0 to 18 years)

c) Cystinuria-dissolution and prevention of cystine stones in adults and children (0 to 18 years)

d) Lead poisoning in adults and children (0 to 18 years)

e) Chronic active hepatitis in adults

 

4.2 Posology and method of administration

Posology

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

As the smallest available tablet is 125mg, this might not be suitable for very young children.

a) Rheumatoid arthritis

Adults: A dose of 125-250mg daily for the initial 4 week period. Increase by the same amount every 4 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 500-750mg daily in divided dosages. A few patients may require up to 1500mg daily to obtain benefit.

When clinical assessment shows that suppression of disease activity has been achieved, the dose should be kept at this maintenance level for six months, thereafter reducing the daily dosage by 125 to 250mg amounts every 12 weeks may be attempted. Relapse may occur following withdrawal or when an inadequate dose level is reached, usually within three months, but most patients respond to further courses of penicillamine.

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.

Elderly: Increased toxicity unrelated to renal function occurs in the elderly. Initial dose should not exceed 125mg daily for the first month, increasing by similar increments every four to twelve 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”).

Renal Insufficiency: Penicillamine therapy should be initiated at a low dose with intervals between dose increases of at least 12 weeks. Fortnightly monitoring for toxicity is mandatory throughout treatment for rheumatoid arthritis.

(b) Wilson's disease

D-penicillamine is a copper-chelating agent, and is most effectively used in conjunction with a low-copper diet (below 1 mg of copper per day). Patients must be maintained in negative copper balance and the minimum dose of penicillamine required to achieve this should be given.

Dosage:

Adults: 1500 to 2000mg daily in divided doses. The optimum dose to achieve a negative copper balance (measured by analysis of 24 hour urinary copper excretion and subsequently by monitoring free copper in the serum) should be chosen. The dose may be reduced to 750-1000 mg daily when disease control is achieved as evidenced by urinary copper excretion. A dose of 2000mg daily should not be continued for more than one year.

Children: 20mg/kg/day in two or three divided doses, given 1 hour before meals. For older children (>12 years) the usual maintenance dose is 0.75-1g daily.

Elderly: Up to 20 mg per kg body weight daily in divided doses. The dosage should be adjusted to minimal level necessary achieve disease control.

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: For the treatment of cystinuria or cystine stones, 1000–3000mg daily in divided doses, adjusted to maintain urinary cystine below 200mg/litre. Maintain adequate fluid intake of 3 litres/day to provide a urine flow of 2 ml/min.

ii) Prevention of cystine stones

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

Children: 20 to 30mg/kg/day in two or three divided doses, given 1 h prior to meals, adjusted to maintain urinary cystine levels below 200mg/litre.

Elderly: The minimum dose which maintains urinary excretion of cystine below 200 mg/L.

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 penicillamine 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: Daily oral dose of 1000-1500mg in divided doses until urinary lead is stabilised at less than 0.5 mg/day.

Children: Penicillamine should only be used in cases where blood lead levels <45mcg/dL. A total of 15-20mg/kg/day in 2-3 doses should be used.

Elderly: 20mg per kg body weight daily in divided doses until urinary lead is stabilised at less than 0.5mg/day.

e) Chronic Active Hepatitis

Adults: Penicillamine is intended for the maintenance treatment of chronic active hepatitis. The diagnosis should be based on a history of at least three months duration with features of chronic aggressive hepatitis, with or without cirrhosis. Treatment with penicillamine should not be commenced until the disease process has been brought under control, initially by treatment with corticosteroids. Disease control should be evidenced by biochemical analysis of liver function to include evaluation of serum bilirubin and transaminase activity.

Penicillamine therapy should be commenced with 500mg daily, in divided doses, increasing gradually over three months to the maintenance dose of 1250mg daily. Concurrently, the dosage of corticosteroids should be reduced and phased out over a three-month period. Throughout therapy, liver function tests should be carried out at suitable intervals for assessment of disease status.

Children: The safety and efficacy of penicillamine in children less than 18 years with chronic active hepatitis have not been established. No data are available.

Elderly: Not recommended.

Method of administration

For oral administration.

 

4.3 Contraindications

Hypersensitivity to penicillamine or any of the ingredients.

Penicillamine is contraindicated in patients with moderate or severe renal insufficiency, lupus erythematosus, a history of penicillamine induced agranulocytosis, aplastic anaemia or severe thrombocytopenia.

 

4.4 Special warnings and precautions for use

Penicillamine should not be given with other drugs capable of causing similar serious haematological or renal adverse effects, for example gold salts, chloroquine, clozapine or hydroxychloroquine, or immunosuppressive drugs.

Patients who are allergic to penicillin may react similarly to penicillamine, but cross-sensitivity appears to be rare.

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 (see Section 4.5, “Interaction with other medicinal products and other forms of interaction”).

Concomitant oral iron, digoxin or antacid therapy should not be given within 2 hours of taking penicillamine (see Section 4.5, “Interactions with Other Medicinal Products and Other forms of Interaction”).

In general the elderly are more likely to have adverse effects.

Because of the potential for serious haematological and renal adverse reactions to occur at any time full blood count and urinalysis should be performed weekly for at least the first 2 months of therapy, (or after any change in dose) and should be repeated monthly thereafter. In cystinuria or Wilson's disease, longer intervals may be adequate.

Patients should be instructed to report promptly the development of signs and symptoms of granulocytopaenia and/or thrombocytopenia such as fever, chills, sore throat, easy bruising or unexplained bleeding, mouth ulcers or rashes. Laboratory tests should be repeated in this case.

Consider withdrawing therapy if platelet count falls below 120 000/mm³ or WBC below 2500/mm³, or if either parameter shows 3 successive falls within the reference range. Therapy can be re-introduced at a lower dose, when the count returns to normal, but should be discontinued permanently if neutropaenia or thrombocytopenia recurs.

Similarly, proteinuria and/or haematuria may be warning signs of glomerulonephritis. In some patients the proteinuria disappears with continued therapy but close observation is essential and therapy should be discontinued if there is heavy or increasing proteinuria or significant haematuria.

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.

With the exception of Wilson's disease, patient's platelet and white cell counts must be normal before commencing treatment. A low platelet or white cell count is not a contra-indication to commence treatment of Wilson's disease. Treatment should be discontinued however, if a low initial count falls further and/or excessive bruising or petechial haemorrhages occur. Liver function tests should be carried out at a frequency determined by the clinical setting (e.g. chronic active hepatitis will require more frequent monitoring.

Concomitant use of NSAIDs and other nephrotoxic drugs may increase the risk of renal damage (see Section 4.5, “Interaction with other medicinal products and other forms of interaction”).

Antihistamines, corticosteroids, or temporary reduction of dose will control allergic phenomena (see Section 4.8 “Undesirable effects”) occurring early, unless severe.

In the treatment of rheumatoid arthritis, response to penicillamine is often slow and the use of existing analgesics, anti-inflammatories or steroids should be continued and later gradually withdrawn, subject to patient improvement.

Pyridoxine 25 mg daily may be given to patients taking penicillamine for long periods, especially if they are on a restricted diet, (e.g. Wilson's disease or cystinuria) since penicillamine increases the requirement for this vitamin (see Section 4.5, “Interactions with Other Medicinal Products and Other forms of Interaction”).

It has been suggested that doses of penicillamine should be reduced to 250 mg daily for 6 weeks prior to elective surgery because of possible effects of penicillamine on collagen and elastin (and thereby on wound healing).

Reversible loss of taste may occur. Mineral supplements to overcome this are not recommended (see Section 4.8 “Undesirable effects”).

Haematuria is rare but if it occurs in the absence of renal stones or other known cause, treatment should be stopped immediately (see Section 4.8 “Undesirable effects”).

A late rash, described as "acquired epidermolysis bullosa" and "penicillamine dermopathy" may occur, after several months or years of therapy and may necessitate a reduction in dosage (see Section 4.8 “Undesirable effects”).

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 (see section 4.8 “Undesirable effects”).

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 (see section 4.8 “Undesirable effects”).

Breast enlargement has been reported as a rare complication of penicillamine therapy in both women and men (see Section 4.8 “Undesirable effects”). Danazol has been used successfully to treat breast enlargement which does not regress on drug discontinuation.

 

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant oral iron or antacids should not be given within 2 hours of taking penicillamine as oral absorption of penicillamine may be reduced. Penicillamine should not be given concurrently with iron or other heavy metals with which it may form complexes. (See section 4.4 “Special warnings and precautions for use”).

Concomitant digoxin should not be given within 2 hours of taking penicillamine as oral absorption of digoxin may be reduced.

Concomitant use of NSAID's 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 is not recommended (See section 4.4 “Special warnings and precautions for use”).

It should not be used in patients who are receiving concurrent gold therapy, antimalarials, immunosuppressive or cytotoxic drugs, clozapine, oxyphenbutazone or phenylbutazone since these drugs have a propensity to cause similar serious haematologic and/or renal adverse reactions.

Coadministration with levodopa may result in elevated levodopa levels.

Coadministration with zinc may result in decreased penicillamine levels; absorption of zinc may also be reduced by penicillamine.

Pyridoxine 25 mg daily may be given to patients taking penicillamine for long periods, especially if they are on a restricted diet, (e.g. Wilson's disease or cystinuria) since penicillamine increases the requirement for this vitamin (see Section 4.4 “Special warnings and precautions for use”).

 

4.6 Fertility, pregnancy and lactation

Pregnancy

The safety of penicillamine in pregnancy has not been established. (See Section 5.3, “Preclinical Safety Data”). It has been shown to be teratogenic in rats when given in doses several times higher than those administered to humans. Penicillamine should be used in pregnancy only when the expected benefits outweigh the risks of discontinuing the medication.

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.

Breast-feeding

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

 

4.7 Effects on ability to drive and use machines

Not known.

 

4.8 Undesirable effects

Both the frequency and severity of many side-effects and adverse reactions to penicillamine are found to be dose-related and vary according to the nature of the disease under treatment, hence the importance of initiating therapy at low doses and gradually increasing the quantity of drug given to optimum level.

The most common side-effects are thrombocytopenia and proteinuria. Thrombocytopenia occurs commonly. It may occur any time during treatment and is usually reversible (see Section 4.4 “Special Warnings and Precautions for use”). Proteinuria occurs in up to 30% of patients and is partially dose-related (see Section 4.4 “Special Warnings and Precautions for use”).

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: Very common (> 1/10), Common (1/100, < 1/10), Uncommon (1/1000, < 1/100), Rare (1/10,000, < 1/1000), Very rare (< 1/10,000), including isolated reports. Not known (where no valid estimate of the incidence has been derived)

Blood and lymphatic system disorders:

Common: Thrombocytopenia

Not known: Neutropenia⁸, agranulocytosis¹, aplastic anaemia¹, haemolytic anaemia, leucopoenia

Immune system disorders:

Rare: Allergic reactions including hypersensitivity

Metabolism and nutrition disorders:

Not known: Anorexia²

Psychiatric disorders:

Not known: Confusion²

Nervous system disorders:

Not known: Loss of taste⁴, headache², dizziness²

Eye disorders:

Not known: Abnormal vision²

Ear and labyrinth disorders:

Rare: Deafness

Vascular disorders:

Not known: Pulmonary haemorrhage

Respiratory, thoracic and mediastinal disorders:

Not known: Dyspnoea, pleural effusion, alveolitis, pulmonary fibrosis, bronchiolitis, pneumonitis,

Gastrointestinal disorders:

Rare: Mouth ulceration, stomatitis, glossitis

Not known: Pancreatitis, nausea², vomiting², diarrhoea²

Hepatobiliary disorders:

Not known: Cholestatic jaundice

Skin and subcutaneous tissue disorders:

Rare: Alopecia, pseudoxanthoma elasticum, elastosis perforans, skin laxity

Not known: Rash², urticarial reactions³, acquired epidermolysis bullosa⁶, penicillamine dermopathy⁶, dermatomyositis, pemphigus, Stevens-Johnson syndrome, yellow nail syndrome

Musculoskeletal, connective tissue and bone disorders:

Not known: Drug induced lupus erythamatosus, myasthenia gravis, polymyositis, rheumatoid arthritis

Renal and urinary disorders:

Very common: Proteinuria

Rare: Haematuria⁵

Not known: Nephrotic syndrome, glomerulonephritis, Goodpasture's syndrome

Reproductive system and breast disorders:

Rare: Breast enlargement⁷

General disorders and administration site conditions:

Not known: Fever²

¹Deaths from agranulocytosis and aplastic anaemia have occurred

²Nausea, anorexia, fever, rash, vomiting, diarrhoea, headaches, dizziness, abnormal vision and confusion may occur early in therapy especially when full doses are given from the start

³Penicillamine may cause allergic reactions such as urticaria and erythema accompanied by hyperpyrexia. Transient rashes and fever may occur early in therapy; if persistent, antihistamines or temporary withdrawal of treatment with or without a short course of steroids may be necessary. Penicillamine may be re-introduced at a lower dosage. If steroids are given, penicillamine should be reintroduced before steroid withdrawal.

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

⁴Reversible loss of taste may occur. Mineral supplements to overcome this are not recommended (See section 4.4 “Special Warnings and Precautions for Use”).

⁵Haematuria may occur rarely, but if it occurs in the absence of renal stones or other known cause, treatment should be stopped immediately (see section 4.4 special warnings and precautions for use).

⁶ A late rash, described as "acquired epidermolysis bullosa" and "penicillamine dermopathy" may occur, after several months or years of therapy and may necessitate a reduction in dosage (see Section 4.4 “Special Warnings and Precautions for Use”).

⁷Breast enlargement has been reported as a rare complication of penicillamine therapy in both women and men (see Section 4.4, “Special Warnings and Precautions for Use”).

⁸ Neutropenia may occur at any time during treatment and is usually reversible (see Section 4.4 “Special Warnings and Precautions for Use”).

Iron deficiency may occur in menstruating women.

The development of septic arthritis in patients with rheumatoid arthritis has been linked to the use of DMARDS, including penicillamine (see section 4.4 “Special warnings and Precautions for use”)

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 (see Section 4.4 “Special warnings and Precautions for use”).

Reporting of suspected adverse reactions

Reporting suspect adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

 

4.9 Overdose

No instances of adverse reactions to an overdose of penicillamine have been recorded and no specific measures are indicated. Treatment of overdosage is symptomatic and withdrawal of the drug is necessary if serious side effects as mentioned above occur.

 

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: M01C C

Penicillamine is an effective chelator of copper, zinc, mercury and lead; both in-vivo and in-vitro and promotes their excretion in urine. It is effective in diseases caused by toxic levels of these metals e.g. Wilson's disease, (Hepatolenticular degeneration), in conjunction with a low copper diet, to promote the excretion of copper.

Penicillamine forms a disulphide bond with cystine (penicillamine-cystine disulphide), which is much more soluble than cystine and more easily excreted and is therefore useful in the treatment of cystinuria and the associated nephrolithiasis. By reducing urinary concentrations of cystine, penicillamine prevents the formation of calculi and promotes the gradual dissolution of existing calculi.

Penicillamine may be used to treat asymptomatic lead intoxication.

Penicillamine has been shown to be effective in the treatment of rheumatoid arthritis not adequately controlled by NSAID therapy, an effect probably not associated with its metal binding properties.

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.

 

5.2 Pharmacokinetic properties

Absorption

Penicillamine is a thiol-group containing chelating agent, variably absorbed from the gastrointestinal tract. Penicillamine is rapidly absorbed from the gastro-intestinal tract and peak plasma levels are reached about one hour after dosing.

Distribution

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.

Biotransformation

Penicillamine is not extensively metabolised in man.

Elimination

The drug is rapidly excreted in urine; however traces remain in the plasma after a single dose for up to 48 hours due to extensive protein binding. Penicillamine is eliminated primarily by metabolism to the disulphide which is excreted in the urine together with a small proportion of unchanged drug. Some of the dose is excreted as a penicillamine copper complex and some as the S-methyl derivative.

 

5.3 Preclinical safety data

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.

 

6. Pharmaceutical particulars

6.1 List of excipients

Each tablet contains the following inactive ingredients:

Tablet core:

Maize starch, silicon dioxide, disodium edetate, poly(1-vinyl-2-pyrrolidone), microcrystalline cellulose, talc, magnesium stearate, mannitol, gelatin

Tablet coating:

Talc, polyethylene glycol, titanium dioxide, copolymerisate of ethyl acrylate-methyl acrylate (2 + 1), polysorbate, sodium carboxymethylcellulose and simethicone

 

6.2 Incompatibilities

Not known.

 

6.3 Shelf life

60 months.

 

6.4 Special precautions for storage

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

 

6.5 Nature and contents of container

Polypropylene bottles with screw caps

Pack size: 4 or 100 tablets.

Tamper-evident pots with polyethylene caps and polypropylene tubs. A low-density polyethylene bag contains the leaflet in the pot.

Pack size: 56 or 100 tablets.

Not all pack types of pack sizes may be marketed.

 

6.6 Special precautions for disposal and other handling

None

 

7. Marketing authorisation holder

Kent Pharmaceuticals Limited,

Wotton Road, Ashford, Kent,

TN23 6LL, United Kingdom

 

8. Marketing authorisation number

PL 08215/0058

 

9. Date of first authorisation/renewal of the authorisation

30/04/2003

 

10. Date of revision of the text

29/08/2020