PENICILLAMINE

Clinical safety rating: caution

Comprehensive clinical and safety monograph for PENICILLAMINE (PENICILLAMINE).

How it works

Chelates heavy metals (copper, mercury, lead, arsenic) forming soluble complexes excreted renally; also reduces cystine formation in cystinuria by disulfide exchange; immunosuppressive effects via inhibition of T-cell function and collagen synthesis.

What the body does with it

Metabolism	Hepatic metabolism to S-methyl-penicillamine and penicillamine disulfide; also undergoes renal excretion.
Excretion	Renal: ~80% as unchanged drug and metabolites; fecal: ~20% (via biliary elimination).
Half-life	Terminal half-life: 1.5–2 hours for penicillamine; after chronic dosing, a slower phase (t1/2 ~40 hours) appears due to tissue binding. Clinical context: Dosing interval typically 6–8 hours; accumulation may occur in renal impairment.
Protein binding	~80% bound to plasma proteins, primarily albumin.
Volume of Distribution	Vd: 0.1–0.2 L/kg; indicates distribution mainly in extracellular fluid and limited tissue penetration, though accumulates in skin and connective tissue.
Bioavailability	Oral: 40–70% (variable due to food and metal ions).
Onset of Action	Oral: Effects on urinary cystine excretion occur within 2–4 hours; clinical benefit in rheumatoid arthritis or Wilson's disease may take weeks to months.
Duration of Action	Oral: Reduction in cystine excretion persists for 6–12 hours after a single dose; for rheumatoid arthritis, effect lasts days to weeks with continued dosing.

Classification & Brands

Dosing & administration

250-500 mg orally 4 times daily, with a maximum of 2 g/day; for rheumatoid arthritis, initial dose 125-250 mg/day, increase by 125-250 mg every 1-3 months to usual maintenance of 500-750 mg/day in divided doses.

Dosage form	CAPSULE
Renal impairment	CrCl >=50 mL/min: no adjustment; CrCl 30-49 mL/min: reduce dose by 50%; CrCl 10-29 mL/min: reduce dose by 75%; CrCl <10 mL/min: avoid use.
Liver impairment	No specific adjustments recommended; use with caution in severe hepatic impairment.
Pediatric use	For Wilson disease: 250 mg/m²/day orally in divided doses; for cystinuria: 30 mg/kg/day in divided doses; for rheumatoid arthritis: 2.5-5 mg/kg/day, titrated slowly.
Geriatric use	Initiate at low end of dosing range; monitor renal function closely; increased risk of hematologic and autoimmune adverse effects.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for PENICILLAMINE (PENICILLAMINE).

Breastfeeding	Excreted in breast milk; M/P ratio approximately 0.1. Low concentrations are present; however, due to potential adverse effects (e.g., rash, bone marrow suppression), caution is advised. Consider monitoring infant for rash or blood dyscrasias.
Teratogenic Risk	First trimester: Known teratogen; associated with cutis laxa, congenital hip dislocation, and other skeletal abnormalities. Contraindicated unless treatment for Wilson disease or cystinuria. Second/third trimesters: Risk of fetal connective tissue defects; avoid unless essential.

Warnings & precautions

■ FDA Black Box Warning

None explicitly issued by FDA.

Side Effect Profile

Serious Effects

Absolute Contraindications

History of aplastic anemia or agranulocytosis, severe renal insufficiency, pregnancy (especially first trimester), breastfeeding, hypersensitivity to penicillamine or penicillin.

Clinical Precautions

Precautions

Bone marrow suppression (leukopenia, thrombocytopenia, aplastic anemia), proteinuria/nephrotic syndrome, autoimmune reactions (myasthenia gravis, Goodpasture's syndrome, lupus-like syndrome), severe skin reactions (toxic epidermal necrolysis), hepatotoxicity, cross-allergenicity with penicillin. Requires monitoring of CBC, urinalysis, liver function.

Clinical Tips & Counseling

Drug interactions

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PENICILLAMINE

Clinical safety rating: caution

Comprehensive clinical and safety monograph for PENICILLAMINE (PENICILLAMINE).

How it works

What the body does with it

Metabolism	Hepatic metabolism to S-methyl-penicillamine and penicillamine disulfide; also undergoes renal excretion.
Excretion	Renal: ~80% as unchanged drug and metabolites; fecal: ~20% (via biliary elimination).
Half-life	Terminal half-life: 1.5–2 hours for penicillamine; after chronic dosing, a slower phase (t1/2 ~40 hours) appears due to tissue binding. Clinical context: Dosing interval typically 6–8 hours; accumulation may occur in renal impairment.
Protein binding	~80% bound to plasma proteins, primarily albumin.
Volume of Distribution	Vd: 0.1–0.2 L/kg; indicates distribution mainly in extracellular fluid and limited tissue penetration, though accumulates in skin and connective tissue.
Bioavailability	Oral: 40–70% (variable due to food and metal ions).
Onset of Action	Oral: Effects on urinary cystine excretion occur within 2–4 hours; clinical benefit in rheumatoid arthritis or Wilson's disease may take weeks to months.
Duration of Action	Oral: Reduction in cystine excretion persists for 6–12 hours after a single dose; for rheumatoid arthritis, effect lasts days to weeks with continued dosing.

Classification & Brands

Dosing & administration

Dosage form	CAPSULE
Renal impairment	CrCl >=50 mL/min: no adjustment; CrCl 30-49 mL/min: reduce dose by 50%; CrCl 10-29 mL/min: reduce dose by 75%; CrCl <10 mL/min: avoid use.
Liver impairment	No specific adjustments recommended; use with caution in severe hepatic impairment.
Pediatric use	For Wilson disease: 250 mg/m²/day orally in divided doses; for cystinuria: 30 mg/kg/day in divided doses; for rheumatoid arthritis: 2.5-5 mg/kg/day, titrated slowly.
Geriatric use	Initiate at low end of dosing range; monitor renal function closely; increased risk of hematologic and autoimmune adverse effects.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for PENICILLAMINE (PENICILLAMINE).

Breastfeeding	Excreted in breast milk; M/P ratio approximately 0.1. Low concentrations are present; however, due to potential adverse effects (e.g., rash, bone marrow suppression), caution is advised. Consider monitoring infant for rash or blood dyscrasias.
Teratogenic Risk	First trimester: Known teratogen; associated with cutis laxa, congenital hip dislocation, and other skeletal abnormalities. Contraindicated unless treatment for Wilson disease or cystinuria. Second/third trimesters: Risk of fetal connective tissue defects; avoid unless essential.

Warnings & precautions

■ FDA Black Box Warning

None explicitly issued by FDA.

Side Effect Profile

Serious Effects

Absolute Contraindications

History of aplastic anemia or agranulocytosis, severe renal insufficiency, pregnancy (especially first trimester), breastfeeding, hypersensitivity to penicillamine or penicillin.