Included as part of the PRECAUTIONS section.
Fatal overdoses, both accidental and intentional, have
been reported in adults and children who have ingested colchicine [See OVERDOSAGE].
MITIGARE® should be kept out of the reach of children.
Myelosuppression, leukopenia, granulocytopenia,
thrombocytopenia, pancytopenia, and aplastic anemia have been reported with
colchicine used in therapeutic doses.
Interactions With CYP3A4 And P-gp Inhibitors
Because colchicine is a substrate for both the CYP3A4
metabolizing enzyme and the P-glycoprotein efflux transporter, inhibition of
either of these pathways may lead to colchicine-related toxicity. Inhibition of
both CYP3A4 and P-gp by dual inhibitors such as clarithromycin has been
reported to produce life-threatening or fatal colchicine toxicity due to
significant increases in systemic colchicines levels. Therefore, concomitant
use of MITIGARE® and inhibitors of CYP3A4 or P-glycoprotein should be
avoided [See DRUG INTERACTIONS]. If avoidance is not possible, reduced
daily dose should be considered and the patient should be monitored closely for
colchicine toxicity. Use of MITIGARE® in conjunction with drugs that
inhibit both P-gp and CYP3A4 is contraindicated in patients with renal or hepatic
impairment [See CONTRAINDICATIONS].
Neuromuscular toxicity and rhabdomyolysis have been
reported from chronic treatment with colchicines in therapeutic doses,
especially in combination with other drugs known to cause this effect. Patients
with impaired renal function and elderly patients (even those with normal renal
and hepatic function) are at increased risk. Once colchicine treatment is
ceased, the symptoms generally resolve within 1 week to several months.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
If a dose of MITIGARE® is missed, advise the
patient to take the dose as soon as possible and then return to the normal
dosing schedule. However, if a dose is skipped, the patient should not double
the next dose.
Advise the patient that fatal overdoses, both accidental
and intentional, have been reported in adults and children who have ingested
colchicine. MITIGARE® should be kept out of the reach of children.
Advise patients that bone marrow depression with
agranulocytosis, aplastic anemia, and thrombocytopenia may occur with MITIGARE®.
Drug And Food Interactions
Advise patients that many drugs or other substances may
interact with MITIGARE® and some interactions could be fatal.
Therefore, patients should report to their healthcare provider all of the current
medications they are taking, and check with their healthcare provider before
starting any new medications, including short-term medications such as
antibiotics. Patients should also be advised to report the use of
non-prescription medication or herbal products. Grapefruit and grapefruit juice
may also interact and should not be consumed during treatment with MITIGARE®.
Advise patients that muscle pain or weakness, tingling or
numbness in fingers or toes may occur with MITIGARE® alone or when it
is used with certain other drugs. Patients developing any of these signs or
symptoms must discontinue MITIGARE® and seek medical evaluation
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity studies of colchicine have not been
conducted. Due to the potential for colchicine to produce aneuploid cells
(cells with an unequal number of chromosomes), colchicine presents a theoretical
increased risk of malignancy.
Published studies demonstrated that colchicine was
negative for mutagenicity in the bacterial reverse mutation assay. However, in
vitro chromosomal aberration assays demonstrated the formation of micronuclei
following colchicine treatment. Because published studies demonstrated that colchicines
induces aneuploidy through the process of mitotic nondisjunction without
structural DNA changes, colchicine is not considered clastogenic, although
micronuclei are formed.
Impairment Of Fertility
There were no studies of the effects of MITIGARE® on
fertility. However, published nonclinical studies have demonstrated that
colchicine-induced disruption of microtubule formation affects meiosis and
mitosis. Published reproductive studies with colchicine reported abnormal sperm
morphology and reduced sperm counts in males, and interference with sperm
penetration, second meiotic division, and normal cleavage in females.
Case reports and epidemiology studies in human male
subjects on colchicine therapy indicate that infertility from colchicine is
rare. A case report indicated that azoospermia was reversed when therapy was
stopped. Case reports and epidemiology studies in female subjects on colchicine
therapy have not established a clear relationship between colchicine use and
Use In Specific Populations
Use In Pregnancy
Pregnancy Category C. There are no adequate and
well-controlled studies with MITIGARE® in pregnant women. Colchicine
crosses the human placenta. Developmental studies in animals were not conducted
with MITIGARE® , however published animal reproduction and development
studies with colchicine demonstrated embryofetal toxicity, teratogenicity, and
altered postnatal development at exposures within or above the clinical
therapeutic range. Colchicine should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Labor And Delivery
The effect of colchicine on labor and delivery is
Use In Nursing Mothers
Colchicine is excreted into human milk. Limited information
suggests that infants exclusively breastfed receive less than 10 percent of the
maternal weight-adjusted dose. While there are no published reports of adverse
effects in breast-feeding infants of mothers taking colchicine, colchicine can
affect gastrointestinal cell renewal and permeability. Caution should be
exercised and breastfeeding infants should be observed for adverse effects when
MITIGARE® is administered to a nursing woman.
Gout is rare in pediatric patients; the safety and effectiveness
of MITIGARE® in pediatric patients has not been evaluated in controlled
Because of the increased incidence of decreased renal
function in the elderly population, and the higher incidence of other co-morbid
conditions in the elderly population requiring the use of other medications,
reducing the dosage of colchicine when elderly patients are treated with colchicines
should be carefully considered.
No dedicated pharmacokinetic study has been conducted
using MITIGARE® in patients with varying degrees of renal impairment.
Colchicine is known to be excreted in urine in humans and the presence of severe
renal impairment has been associated with colchicine toxicity. Urinary
clearance of colchicines and its metabolites may be decreased in patients with
impaired renal function. Dose reduction or alternatives should be considered
for the prophylaxis of gout flares in patients with severe renal impairment.
Colchicine is not effectively removed by hemodialysis. Patients who are
undergoing hemodialysis should be monitored carefully for colchicine toxicity.
No dedicated pharmacokinetic study using MITIGARE®
Â has been conducted in patients with varying degrees of hepatic impairment.
Colchicine is known to be metabolized in humans and the presence of severe
hepatic impairment has been associated with colchicine toxicity. Hepatic
clearance of colchicine may be significantly reduced and plasma half-life
prolonged in patients with chronic hepatic impairment.
Dose reduction or alternatives should be considered for
the prophylaxis of gout flares in patients with severe hepatic impairment.