Microsoft word - leukocel_package_insert.doc

LEUKOCEL
Hydroxyurea capsules, USP 500 mg

Each capsule contains
Hydroxyurea
Excipients

DESCRIPTION
LEUKOCEL (Hydroxyurea capsules, USP) is available for oral use as capsules
providing 200 mg, 300 mg, and 400 mg Hydroxyurea. Inactive ingredients: citric acid, gelatin, lactose, magnesium stearate, sodium phosphate, titanium dioxide and capsule colorants: FD&C Blue #1 and FD&C Green #3 (200 mg capsules); D&C Red #28, D&C Red #33 and FD&C Blue #1 (300 mg capsules); D&C Red #28, D&C Red #33 and D&C Yellow #10 (400 mg capsules). Leukocel is an essentially tasteless, white crystalline powder. Its structural formula is:
CLINICAL PHARMACOLOGY
Mechanism of Action
The precise mechanism by which Leukocel produces its cytotoxic and cytoreductive effects is not known. However, various studies support the hypothesis that Leukocel causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor without interfering with the synthesis of ribonucleic acid or of protein. The mechanisms by which Leukocel produces its beneficial effects in patients with sickle cell anemia (SCA) are uncertain. Known pharmacologic effects of Leukocel that may contribute to its beneficial effects include increasing hemoglobin F levels in RBCs, decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium.
Pharmacokinetics
Absorption
Leukocel is readily absorbed after oral administration. Peak plasma levels
are reached in 1 to 4 hours after an oral dose. With increasing doses, disproportionately greater mean peak plasma concentrations and AUCs are observed. There are no data on the effect of food on the absorption
Distribution
Leukocel distributes rapidly and widely in the body with an estimated
volume of distribution approximating total body water. Plasma to ascites fluid ratios range from 2:1 to 7.5:1. Leukocel concentrates in leukocytes and erythrocytes.
Metabolism
Up to 60% of an oral dose undergoes conversion through metabolic
pathways that are not fully characterized. One pathway is probably saturable hepatic metabolism. Another minor pathway may be degradation by urease found in intestinal bacteria. Acetohydroxamic acid was found in the serum of three leukemic patients receiving Leukocel and may be formed from hydroxylamine resulting from action of urease on Leukocel.
Excretion
Excretion of Leukocel in humans is likely a linear first-order renal process. In
adults with SCA, mean cumulative urinary recovery of Leukocel was about 40% of the administered dose.
Special Populations
Geriatric, Gender, Race No information is available regarding pharmacokinetic differences due to age, gender or race.
Pediatric
No pharmacokinetic data are available in pediatric patients treated with
Leukocel for SCA.
Renal Insufficiency
As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of Leukocel in patients with renal impairment. In adult patients with sickle cell disease, an open-label, nonrandomized, single-dose, multicenter study was conducted to assess the influence of renal function on the pharmacokinetics of Leukocel. Patients in the study with normal renal function (creatinine clearance (CrCl)>80 mL/min), mild (CrCl 50-80 mL/min), moderate (CrCl=30-<50mL/min), or severe (<30 mL/min) renal impairment received Leukocel as a single oral dose of 15 mg/kg, achieved by using combinations of the 200 mg, 300 mg, or 400 mg capsules. Patients with end-stage renal disease (ESRD) received two doses of 15 mg/kg separated by 7 days, the first was given following a 4-hour hemodialysis session, the second prior to hemodialysis. In this study the mean exposure (AUC) in patients whose creatinine clearance was <60mL/min (or ESRD) was approximately 64% higher than in patients with normal renal function. The results suggest that the initial dose of Leukocel should be reduced when used to treat patients with renal impairment. (See PRECAUTIONS and DOSAGE AND
ADMINISTRATION.)
The table below describes the recommended dosage modification.
Close monitoring of hematologic parameters is advised in these patients. There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients.
INDICATIONS AND USAGE
Leukocel (Hydroxyurea capsules, USP) is indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in adult patients with sickle cell anemia with recurrent moderate to severe
painful crises (generally at least 3 during the preceding 12 months).
CONTRAINDICATIONS
Leukocel is contraindicated in patients who have demonstrated a
previous hypersensitivity to Leukocel or any other component of its
formulation.
WARNINGS
Leukocel is a cytotoxic and myelosuppressive agent. Leukocel L should
not be given if bone marrow function is markedly depressed, as indicated
by neutrophils below 2000 cells/mm3; a platelet count below 80,000/mm3;
a hemoglobin level below 4.5 g/dL; or reticulocytes below 80,000/mm3
when the hemoglobin concentration is below 9 g/dL. Neutropenia is generally the first and most common manifestation of hematologic
suppression. (See DOSAGE AND ADMINISTRATION.) Thrombocytopenia
and anemia occur less often, and are seldom seen without a preceding
leukopenia. Recovery from myelosuppression is usually rapid when therapy is interrupted. Leukocel causes macrocytosis, which may mask the incidental development of folic acid deficiency. Prophylactic administration of folic acid is recommended. Fatal and nonfatal pancreatitis have occurred in HIV-infected patients during therapy with Leukocel and didanosine, with or without stavudine. Hepatotoxicity and hepatic failure resulting in death have been reported during post-marketing surveillance in HIV-infected patients treated with Leukocel and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of Leukocel, didanosine, and stavudine. Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected patients receiving Leukocel in combination with antiretroviral agents, including didanosine, with or without stavudine. Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with Leukocel. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. Due to potentially severe clinical outcomes for the cutaneous vasculitic ulcers reported in patients with myeloproliferative disease, Leukocel should be discontinued if cutaneous vasculitic ulcerations develop.
PRECAUTIONS
Therapy with Leukocel (Hydroxyurea capsules, USP) requires close
supervision. Some patients treated at the recommended initial dose of 15 mg/kg/day have experienced severe or life-threatening myelosuppression, requiring interruption of treatment and dose reduction. The hematologic status of the patient as well as kidney and liver function should be determined prior to, and repeatedly during, treatment. Treatment should be interrupted if neutrophil levels fall to <2000/mm3; platelets fall to <80,000/mm3; hemoglobin declines to less than 4.5 g/dL;
or if reticulocytes fall below 80,000/mm3 when the hemoglobin
concentration is below 9 g/dL. Following recovery, treatment may be
resumed at lower doses (see DOSAGE AND ADMINISTRATION).
Leukocel should be used with caution in patients with renal dysfunction.
Data from a single-dose study of the pharmacokinetics of Leukocel in
patients with sickle cell anemia suggest that the initial dose of Leukocel
should be reduced in patients with renal impairment. (See CLINICAL
PHARMACOLOGY:
Special Populations and
DOSAGE AND
ADMINISTRATION.)
Patients must be able to fol ow directions regarding drug administration and their monitoring and care. Leukocel is not indicated for the treatment of HIV infection; however, if HIV-infected patients are treated with Leukocel, and in particular, in combination with didanosine and/or stavudine, close monitoring for signs and symptoms of pancreatitis and hepatotoxicity is recommended. Patients who develop signs and symptoms of pancreatitis or hepatotoxicity should permanently discontinue therapy with Leukocel.
(See WARNINGS and ADVERSE REACTIONS.)

Drug Interactions
There are no data on concomitant use of Leukocel with other drugs in humans.
Clinical Studies
The efficacy of Leukocel in sickle cell anemia was assessed in a large
clinical study (Multicenter Study of Leukocel in Sickle Cell Anemia).1 The study was a randomized, double-blind, placebo-controlled trial that evaluated 299 adult patients (≥18 years) with moderate to severe disease (≥ 3 painful crises yearly). The trial was stopped by the Data Safety Monitoring Committee, after accrual was completed but before the scheduled 24 months of follow up was completed in all patients, based on observations of fewer painful crises among patients receiving Leukocel. Compared to placebo treatment, treatment with Leukocel resulted in a significant decrease in the yearly rate of painful crises, the yearly rate of painful crises requiring hospitalization, the incidence of chest syndrome, the number of patients transfused, and units of blood transfused. Leukocel treatment significantly increased the median time to both first and second painful crises. Although patients with 3 or more painful crises during the preceding 12 months were eligible for the study, most of the benefit in crisis reduction was seen in the patients with 6 or more painful crises during the preceding 12 months. No deaths were attributed to treatment with Leukocel, and none of the patients developed neoplastic disorders during the study. Treatment was permanently stopped for medical reasons in 14 Leukocel treated (2 patients with myelotoxicity) and 6 placebo-treated patients. (See
ADVERSE REACTIONS.)
Fetal Hemoglobin
In patients with SCA treated with Leukocel, fetal hemoglobin (HbF)
increases 4 to 12 weeks after initiation of treatment. In general, average HbF levels correlate with dose and plasma level with possible plateauing at higher dosages. A clear relation between reduction in crisis frequency and increased HbF or F-cell levels has not been demonstrated. The dose-related cytoreductive effects of Leukocel, particularly on neutrophils, was the factor most strongly correlated with reduced crisis frequency.
Carcinogenesis and Mutagenesis
(See Boxed WARNING.) Leukocel is genotoxic in a wide range of test
systems and is thus presumed to be a human carcinogen. In patients
receiving long-term Leukocel for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemia has been reported. It is unknown whether this leukemogenic effect is secondary to Leukocel or is associated with the patient’s underlying disease. Skin cancer has also been reported in patients receiving long-term Leukocel.
Conventional long-term studies to evaluate the carcinogenic potential of
LEUKOCEL have not been performed. However, intraperitoneal
administration of 125-250 mg/kg Leukocel (about 0.6-1.2 times the maximum recommended human oral daily dose on a mg/m2 basis) thrice weekly for 6 months to female rats increased the incidence of mammary tumors in rats surviving to 18 months compared to control. Leukocel is mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells. Leukocel is clastogenic in vitro (hamster cells, human lymphoblasts) and in vivo (SCE assay in rodents, mouse micronucleus assay). Leukocel causes the transformation of rodent embryo cells to a tumorigenic phenotype.
Pregnancy
LEUKOCEL can cause fetal harm when administered to a pregnant
woman. Leukocel has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs and monkeys at doses within 1-fold of the human dose given on a mg/m2 basis. Leukocel is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) in rabbits. Embryo toxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Leukocel crosses the placenta. Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose on a mg/m2 basis) to rats caused growth retardation and impaired learning ability. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Carcinogenesis, Mutagenesis, Impairment of Fertility
See WARNINGS and Boxed WARNING for Carcinogenesis and
Mutagenesis information. Impairment of Fertility: Leukocel administered to male rats at 60 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m2 basis) produced testicular atrophy, decreased spermatogenesis, and significantly reduced their ability to impregnate
Pregnancy
Pregnancy “Category D”. (See WARNINGS.)
Nursing Mothers
Leukocel is excreted in human milk. Because of the potential for serious adverse reactions with Leukocel, a decision should be made either to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Drug Interactions
Prospective studies on the potential for Leukocel to interact with other drugs have not been performed. Information for Patients
(See Patient Information at end of labeling.) Patients should be reminded
that this medication must be handled with care. People who are not
taking LEUKOCEL should not be exposed to it. To decrease the risk of
exposure, wear disposable gloves when handling LEUKOCEL or bottles
containing LEUKOCEL. Anyone handling LEUKOCEL should wash their
hands before and after contact with the bottle or capsules. If the powder
from the capsule is spilled, it should be wiped up immediately with a damp disposable towel and discarded in a closed container, such as a plastic bag. The medication should be kept away from children and pets. Contact your doctor for instructions on how to dispose of outdated capsules. The necessity of monitoring blood counts every two weeks, throughout the duration of therapy, should be emphasized. For additional information, see the accompanying Patient Information leaflet.
ADVERSE REACTIONS
Sickle Cell Anemia
In patients treated for sickle cell anemia in the Multicenter Study of
Leukocel in Sickle Cell Anemia,1 the most common adverse reactions
were hematologic, with neutropenia, and low reticulocyte and platelet
levels necessitating temporary cessation in almost all patients.
Hematologic recovery usually occurred in two weeks. Non-hematologic events that possibly were associated with treatment include hair loss, skin rash, fever, gastrointestinal disturbances, weight gain, bleeding and parvovirus B-19 infection; however, these non-hematologic events occurred with similar frequencies in the Leukocel and placebo treatment groups. Melanonychia has also been reported in patients
Other
Adverse events associated with the use of Leukocel in the treatment of
neoplastic diseases, in addition to hematologic effects include: gastrointestinal symptoms (stomatitis, anorexia, nausea, vomiting, diarrhea, and constipation), and dermatological reactions such as maculopapular rash, skin ulceration, dermatomyositis-like skin changes, peripheral erythema and facial erythema. Hyper pigmentation, atrophy of skin and nails, scaling and violet papules have been observed in some patients after several years of long-term daily maintenance therapy with Leukocel. Skin cancer has been reported. Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with Leukocel. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy (see WARNINGS). Dysuria and
alopecia occur very rarely. Large doses may produce moderate
drowsiness. Neurological disturbances have occurred extremely rarely and were limited to headache, dizziness, disorientation, hallucinations, and convulsions. Leukocel occasionally may cause temporary impairment of renal tubular function accompanied by elevations in serum uric acid, BUN, and creatinine levels. Abnormal BSP retention has been reported. Fever, chil s, malaise, edema, asthenia, and elevation of hepatic enzymes have also been reported. The association of Leukocel with the development of acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever and dyspnea has been rarely reported. Pulmonary fibrosis also has been reported rarely. Fatal and nonfatal pancreatitis and hepatotoxicity, and severe peripheral neuropathy have been reported in HIV-infected patients who received Leukocel in combination with antiretroviral agents, in particular, didanosine plus stavudine. Patients treated with Leukocel in combination
with didanosine, stavudine, and indinavir in Study ACTG 5025 showed a
median decline in CD4 cells of approximately 100/mm3. (See WARNINGS
and PRECAUTIONS.)
OVERDOSAGE
Acute mucocutaneous toxicity has been reported in patients receiving
Leukocel at dosages several times the therapeutic dose. Soreness, violet
erythema, edema on palms and soles followed by scaling of hands and
feet, severe generalized hyper pigmentation of the skin, and stomatitis
have been observed.

DOSAGE AND ADMINISTRATION
To minimize the risk of dermal exposure, always wear impervious gloves
when handling bottles containing Leukocel L (Hydroxyurea capsules, USP)
capsules. This includes all handling activities in clinical settings,
pharmacies, storerooms, and home healthcare settings, including during unpacking and inspection, transport within a facility, and dose preparation and administration. Procedures for proper handling and disposal of cytotoxic drugs should be considered. Several guidelines on this subject have been published.2-9. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Dosage should be based on the patient’s actual or ideal weight, whichever is less. The initial dose of Leukocel is 15 mg/kg/day as a single dose. The patient’s blood count must be monitored every two weeks. (See
WARNINGS.)

If blood counts are in an acceptable range*, the dose may be increased
by 5 mg/kg/day every 12 weeks until a maximum tolerated dose (the
highest dose that does not produce toxic** blood counts over 24
consecutive weeks), or 35 mg/kg/day, is reached.
If blood counts are between the acceptable range* and toxic**, the dose
is not increased.
If blood counts are considered toxic**, Leukocel should be discontinued
until hematologic recovery.
Treatment may then be resumed after reducing the dose by 2.5
mg/kg/day from the dose associated with hematologic toxicity. Leukocel
may then be titrated up or down, every 12 weeks in 2.5 mg/kg/day
increments, until the patient is at a stable dose that does not result in
hematologic toxicity for 24 weeks. Any dosage on which a patient
develops hematologic toxicity twice should not be tried again.
*acceptable range =
Neutrophils ≥2500 cells/mm3,
Platelets ≥95,000/mm3,
Hemoglobin >5.3 g/dL and
Reticulocytes ≥95,000/mm3
If the hemoglobin concentration <9 g/dL.
**toxic =
Hemoglobin <4.5 g/dL and Reticulocytes <80,000/mm3 If the hemoglobin concentration <9 g/dL.
Renal Insufficiency
As renal excretion is a pathway of elimination, consideration should be
given to decreasing the dosage of Leukocel in patients with renal impairment. The results of a single-dose study of the influence of renal function on the pharmacokinetics of Leukocel in adults with sickle cell disease suggest that the initial dose of Leukocel should be reduced by 50% to 7.5 mg/kg/d, when used to treat patients with renal impairment. (See PRECAUTIONS and CLINICAL PHARMACOLOGY.) Close monitoring of
hematologic parameters is advised in these patients.

Hepatic Insufficiency
There are no data that support specific guidance for dosage adjustment
in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients.
HOW SUPPLIED
Leukocel ® (Hydroxyurea capsules, USP)
200 mg capsules packaged in HDPE bottles of 60 with a plastic safety
screw cap. (NDC 0003-6335-17). The cap and body are opaque blue- green. The capsule is marked in black ink on both the cap and body with
“Leukocel” and “6335.”
300 mg capsules packaged in HDPE bottles of 60 with a plastic safety
screw cap. (NDC 0003-6336-17). The cap and body are opaque purple.
The capsule is marked in black ink on both the cap and body with
“Leukocel” and “6336.”
400 mg capsules packaged in HDPE bottles of 60 with a plastic safety
screw cap. (NDC 0003-6337-17). The cap and body are opaque reddish-
orange. The capsule is marked in black ink on both the cap and body
with “Leukocel” and “6337.”


Storage
Store at 25° C (77° F); excursions permitted to 15-30° C (59-86° F) [see USP
Controlled Room Temperature]. Keep tightly closed.
For further Information please write to: CELON LABORATORIES LIMITED
PLOT NO-2, ALEAP INDUSTRIAL ESTATE
NEAR PRAGATHI NAGAR
GAJULARAMARAM
HYDERABAD-500 072

Source: http://www.celonlabs.com/pdf/leukocel_pc.pdf