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].
GLOPERBA 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.
Because colchicine is a substrate for both the CYP3A4
metabolizing enzyme and the P-gp efflux transporter, inhibition of either of
these pathways may lead to colchicine-related toxicity. Inhibition of both
CYP3A4 and P-gp by dual inhibitors (i.e., clarithromycin) has been reported to
produce life-threatening or fatal colchicine toxicity due to significant
increases in systemic colchicine levels. Therefore, concomitant use of GLOPERBA
with inhibitors of both CYP3A4 and P-gp should be avoided. If treatment with
colchicine is necessary, a reduced daily dose should be considered and the
patient should be closely monitored for colchicine toxicity [see DRUG
Use of GLOPERBA in conjunction with drugs that inhibit
both CYP3A4 and P-gp is contraindicated in patients with renal or hepatic
impairment [see CONTRAINDICATIONS].
Colchicine-induced neuromuscular toxicity and
rhabdomyolysis have been reported with chronic treatment 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
stopped, the symptoms generally resolve within one week to several months.
Patient Counseling Information
Advise the patient to read the
FDA-approved patient labeling (Medication Guide).
Patients should be advised to
take GLOPERBA as prescribed, even if they are feeling better. Patients should
not alter the dose or discontinue treatment without consulting with their
doctor. If a dose of GLOPERBA is missed, 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 patients and caregivers
to measure GLOPERBA with an accurate milliliter measuring device. A household
teaspoon is not an accurate measuring device. Advise patients and caregivers to
ask their pharmacist to recommend an appropriate measuring device and for
instructions for measuring the correct dose.
Instruct patient that fatal
overdoses, both accidental and intentional, have been reported in adults and
children who have ingested colchicine. GLOPERBA should be kept out of the reach
Patients should be informed
that bone marrow depression with agranulocytosis, aplastic anemia and
thrombocytopenia may occur with GLOPERBA.
Drug And Food Interactions
Advise patients that many drugs
or other substances may interact with GLOPERBA 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
nonprescription medication or herbal products. Grapefruit and grapefruit juice
may also interact and should not be consumed during GLOPERBA treatment.
Patients should be informed
that muscle pain or weakness, tingling or numbness in fingers or toes may occur
with GLOPERBA alone or when it is used with certain other drugs. Patients
developing any of these signs or symptoms must discontinue GLOPERBA and seek
medical evaluation immediately.
Advise males of reproductive
potential that GLOPERBA may rarely and transiently impair fertility [see Use
In Specific Populations].
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.
Colchicine was negative for mutagenicity in the bacterial
reverse mutation assay. In a chromosomal aberration assay in cultured human
white blood cells, colchicine treatment resulted in the formation of
micronuclei. Since published studies demonstrated that colchicine induces
aneuploidy from the process of mitotic nondisjunction without structural DNA
changes, colchicine is not considered clastogenic, although micronuclei are
Impairment Of Fertility
There were no studies conducted of the effects of
GLOPERBA on fertility. Published nonclinical studies have demonstrated that
colchicine-induced disruption of microtubule formation affects meiosis and
mitosis. Published colchicine reproductive studies have reported abnormal sperm
morphology and reduced sperm counts in males and interference with sperm
penetration, second meiotic division and normal cleavage in females.
Use In Specific Populations
Available human data from published literature on
colchicine use in pregnancy over several decades have not identified any drug
associated risks for major birth defects, miscarriage, or adverse maternal or
fetal outcomes (see Data). Although animal reproduction and development
studies were not conducted with GLOPERBA, published animal reproduction and
development studies indicate that colchicine causes embryofetal toxicity and
altered postnatal development at exposures within or above the clinical
The estimated background risk of major birth defects and
miscarriage for the indicated population is unknown. All pregnancies have a
background risk of birth defect, loss or other adverse outcomes. In the U.S.
general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%,
Available data from published observational studies, case
series, and case reports over several decades do not suggest an increased risk
for major birth defects or miscarriage in pregnant women with rheumatic
diseases (such as rheumatoid arthritis, BehÃ§et's disease, or familial
Mediterranean fever (FMF)) treated with colchicine at therapeutic doses during
pregnancy. Limitations of these data include the lack of randomization and
inability to control for confounders such as underlying maternal disease and maternal
use of concomitant medications.
Colchicine is present in human milk (see Data).
Adverse events in breastfed infants have not been reported in the published
literature after administration of colchicine to lactating women. There are no
data on the effects of colchicine on milk production. The developmental and
health benefits of breastfeeding should be considered along with the mother's
clinical need for GLOPERBA and any potential adverse effects on the breastfed
infant from GLOPERBA or from the underlying maternal condition.
Limited published data from case reports and a small
lactation study demonstrate that colchicine is present in breastmilk. A
systematic review of literature reported no adverse effects in 149 breastfed
children and advised to reconsider breastfeeding if the infant has diarrhea. In
a prospective observational cohort study, no gastrointestinal or other symptoms
were reported in 38 colchicine-exposed breastfed infants.
Females And Males Of Reproductive Potential
Case reports and epidemiology studies in
human male subjects on colchicine therapy indicate that infertility from
colchicine is rare and may be reversible.
Gout is rare in pediatric patients; safety and
effectiveness of GLOPERBA in pediatric patients has not been established.
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
colchicine should be carefully considered [see CLINICAL PHARMACOLOGY].
No dedicated pharmacokinetic study has been conducted
using GLOPERBA 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
colchicine 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 GLOPERBA 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.