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  • CLASSES

    Cytostatic Anti-estrogens

    DEA CLASS

    Rx

    DESCRIPTION

    Pure estrogen-receptor antagonist without any known estrogen agonist effects
    Degrades the estrogen receptor as opposed to blocking it as with tamoxifen
    Used as monotherapy for first- and second-line treatment of advanced breast cancer in postmenopausal women, and in combination with palbociclib or abemaciclib in women with HR-positive, HER2-negative advanced or metastatic breast cancer after disease progression following endocrine therapy

    COMMON BRAND NAMES

    FASLODEX

    HOW SUPPLIED

    FASLODEX Intramuscular Inj Sol: 1mL, 50mg

    DOSAGE & INDICATIONS

    For the treatment of breast cancer.
    For the treatment of hormone receptor (HR)-positive metastatic breast cancer in postmenopausal women with disease progression following endocrine therapy, as monotherapy.
    Intramuscular dosage
    Postmenopausal females

    500 mg intramuscularly as two 250-mg (5 mL) injections, 1 injection in each buttock (gluteal area), on days 1, 15, 29 and once monthly thereafter. Give each injection over 1 to 2 minutes. The median progression-free survival (6.5 months vs. 5.4 months) and overall survival (26.4 months vs. 22.3 months) were significantly improved with fulvestrant 500 mg IM (n = 362) compared with fulvestrant 250 mg IM (n = 374) in postmenopausal women with estrogen-receptor positive advanced breast cancer who experienced disease progression following endocrine therapy in a randomized, double-blind, phase 3 study (the CONFIRM study).

    For the first-line treatment of hormone receptor (HR)-positive metastatic breast cancer in postmenopausal women, in combination with anastrozole†.
    Intramuscular dosage
    Postmenopausal females

    500 mg intramuscularly as two 250-mg (5 mL) injections, 1 injection in each buttock (gluteal area) over 1 to 2 minutes on day 1, followed by 250 mg intramuscularly every 2 weeks for 2 doses then 250 mg intramuscularly every 4 weeks thereafter in combination with anastrozole (1 mg PO once daily) was evaluated in 2 randomized, open label, phase III trials. Treatment was continued until disease progression.

    For the treatment of hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer after disease progression following endocrine-based therapy, in combination with palbociclib.
    Intramuscular dosage
    Adult females

    500 mg intramuscularly as two 250-mg (5 mL) injections, 1 injection in each buttock (gluteal area) over 1 to 2 minutes on days 1, 15, 29, and once monthly thereafter in combination with palbociclib (125 mg PO once daily with food for 21 days, followed by 7 days off, repeated every 28 days) until progressive disease or unacceptable toxicity occurs. Premenopausal and perimenopausal women should also be treated with luteinizing hormone-releasing hormone (LHRH) agonists, according to current clinical practice standards. Coadministration of palbociclib with certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Women (regardless of menopausal status) with endocrine therapy-resistant, HR-positive, HER2-negative advanced breast cancer were randomized to receive palbociclib plus fulvestrant (n = 347) or fulvestrant plus placebo (n = 174) in an international, randomized, double-blind, placebo-controlled clinical trial. Investigator assessed progression-free survival (PFS) was significantly improved in the palbociclib group compared with those who received placebo (9.5 months vs. 4.6 months), with a response duration of 9.3 months and 7.6 months, respectively; results were consistent across subgroups of disease site, sensitivity to prior hormonal therapy, and menopausal status. Investigator-assessed confirmed overall response rate was 24.6% in those treated with palbociclib and fulvestrant, compared with 10.9% in patients who received fulvestrant plus placebo. Overall survival data were not mature at the time of the PFS analysis.

    For the treatment of hormone receptor (HR)-positive, HER2-negative advanced breast cancer in postmenopausal women who have not previously been treated with endocrine therapy, as monotherapy.
    Intramuscular dosage
    Postmenopausal females

    500 mg intramuscularly as two 250-mg (5 mL) injections, 1 injection in each buttock (gluteal area), on days 1, 15, 29 and once monthly thereafter. Give each injection over 1 to 2 minutes. In a randomized, double-blind, placebo-controlled clinical trial (FALCON), the first-line treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer with fulvestrant (n = 230) significantly improved progression-free survival (PFS) compared with anastrozole (n = 232) (16.6 months vs. 13.8 months); median overall survival was not reached in either group. The objective response rate was 46.1% with a median duration of 20 months in the fulvestrant arm, compared with 44.9% and a duration of 13.2 months in the anastrozole arm.

    For the treatment of hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy, in combination with abemaciclib.
    Intramuscular dosage
    Adults

    500 mg intramuscularly as two 250-mg (5 mL) injections, 1 injection in each buttock (gluteal area), on days 1, 15, 29 and once monthly thereafter, in combination with abemaciclib (150 mg by mouth twice daily) until disease progression or unacceptable toxicity. Give each injection over 1 to 2 minutes. Pre- and perimenopausal women should also be treated with a gonadotropin-releasing hormone agonist according to current clinical practice standards. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with fulvestrant plus abemaciclib (n = 446) significantly improved median progression-free survival (PFS) compared with fulvestrant plus placebo (n = 223) in a multicenter, randomized clinical trial of women with HR-positive, HER2-negative metastatic breast cancer with disease progression following adjuvant or metastatic endocrine therapy (16.4 months vs. 9.3 months); both arms were also treated with goserelin for at least 4 weeks prior to starting and continuing for the duration of the study. The objective response rate for patients with measurable disease was 48.1% in the abemaciclib arm (n = 318) compared with 21.3% in the placebo arm (n = 164).

    MAXIMUM DOSAGE

    Adults

    500 mg IM.

    Elderly

    500 mg IM.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment is required in patients with mild hepatic impairment (Child-Pugh class A). In patients with moderate hepatic impairment (Child-Pugh class B), administer 250 mg IM on days 1, 15, 29, and once monthly thereafter. The use of fulvestrant has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intramuscular Administration

    Fulvestrant is given by intramuscular injection into the gluteal area of the buttock; do not give intravenously.
    Administer the injection according to local guidelines for large volume intramuscular injections.
    Use caution at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve; injection site-related sciatica, neuralgia, neuropathic pain, and peripheral neuropathy have been reported.
    For the Faslodex 5 mL per syringe, 2-syringe package, both syringes must be administered to receive the full 500 mg dose.
     
    Intramuscular injection:
    Remove perforated patient record label from syringe.
    Peel open the safety needle (SafetyGlide) outer packaging.
    Hold the syringe upright on the ribbed part; with the other hand, tilt the cap back and forth (do NOT twist) until it disconnects for removal. Pull the cap off in a straight upward direction.
    Attach the SafetyGlide needle to the Luer Lock of the syringe.
    Remove the needle sheath, and expel excess gas from the syringe (a small gas bubble may remain).
    Inject deeply into the gluteal area of the buttock. Aspirate prior to injection to avoid injection into a blood vessel.
    Administer each injection over 1 to 2 minutes.
    After withdrawal of the needle from the patient, push the lever arm completely forward with a single-finger stroke to the activation assisted lever arm, until the needle tip is fully covered. This may cause minimal splatter of fluid that may remain on the needle after injection. If unable to activate the needle protection device, discard immediately into an approved sharps container.
    Repeat these steps for a second syringe, giving each injection in a separate buttock. Rotate injection sites.

    STORAGE

    FASLODEX:
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Intravenous administration, neurologic events, peripheral neuropathy

    Avoid intravenous administration; fulvestrant is given by intramuscular injection into the gluteal area of the buttock. Use caution at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve; injection site-related neurologic events including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy have been reported.

    Hepatic disease

    Increased drug exposure has occurred in patients with moderate hepatic disease (Child Pugh class B); a dose reduction is necessary in these patients. The safety and efficacy of fulvestrant have not been established in patients with severe hepatic impairment (Child Pugh class C), however, the safety profile in patients with mild hepatic impairment is similar to that seen in patients with no hepatic impairment.

    Anticoagulant therapy, coagulopathy, thrombocytopenia

    Because fulvestrant is given intramuscularly (IM), it should not be used or given with caution in patients with underlying coagulopathy, thrombocytopenia, or those receiving anticoagulant therapy. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.

    Laboratory test interference

    Due to structural similarity, fulvestrant can cause a laboratory test interference with estradiol measurement with immunoassay; this may result in falsely elevated estradiol levels.

    Children, infants, neonates

    The efficacy and safety of fulvestrant have not been established in neonates, infants, children, or adolescents. Once monthly intramuscular injections of fulvestrant 4 mg/kg have been studied in 30 female pediatric patients aged 1 to 8 years with progressive precocious puberty secondary to McCune-Albright Syndrome. Patients treated with fulvestrant experienced a reduction in the rate of bone age advancement over the 12 month study period compared to baseline and a reduction in mean growth velocity Z-score compared to baseline. Of the 23 patients with vaginal bleeding at baseline, 35% experienced cessation of bleeding with fulvestrant therapy. No clinically meaningful changes in median Tanner stage, mean uterine volume, mean ovarian volume, or predicted adult height compared to baseline were observed.

    Pregnancy

    Although there are no adequate and well-controlled studies in pregnant women, fetal harm or loss may occur if fulvestrant is administered during pregnancy based on animal studies. Females of child-bearing potential should be advised not to become pregnant while receiving fulvestrant or for one year after the last dose. Woman who become pregnant during treatment with fulvestrant should be informed of the potential risk to the fetus. When fulvestrant was administered to pregnant rats and rabbits during organogenesis, embryo-fetal toxicity (including skeletal malformations and fetal loss) occurred at daily doses of 6% and 30% the maximum recommended human dose based on mg/m2, respectively. Fulvestrant, when given prior to and up to implantation, caused embryonic loss in rats at daily doses that were 0.6% of the maximum recommended human dose on a mg/m2 basis; antiestrogenic effects on embryo-fetal development occurred when fulvestrant was administered during organogenesis at 6% of the human recommended dose. Additionally, an increased incidence of fetal abnormalities and fetal loss occurred in rats exposed to fulvestrant at doses equivalent to the human recommended dose on a mg/m2 basis (tarsal flexure of the hind paw at 2 mg/kg/day) as well as much lower doses (non-ossification of the odontoid and ventral tubercle of the first cervical vertebra at >= 0.1 mg/kg/day). Pregnancy loss also occurred in rabbits when fulvestrant was given during organogenesis at doses equivalent to the human dose on a mg/m2 basis. At lower doses (30% of the human dose), fetal malformations included backwards displacement of the pelvic girdle and 27 pre-sacral vertebrae as well as increases in placental weight and post-implantation loss.

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Counsel patients about reproductive risk and contraception requirements during fulvestrant therapy. Fulvestrant can be teratogenic and embryotoxic if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during treatment and for at least 1 year after the last dose of fulvestrant. Females of reproductive potential should undergo pregnancy testing within 7 days prior to initiation of fulvestrant. Women who become pregnant while receiving fulvestrant should be apprised of the potential hazard to the fetus. In addition, based on animal data, fulvestrant may cause reversible impairment of fertility or infertility in both males and females of reproductive potential.

    Breast-feeding

    According to the manufacturer, breast-feeding should be discontinued during treatment with fulvestrant and for at least 1 year after the last dose because of the potential for serious adverse reactions in a nursing infant from drug exposure. It is not known if fulvestrant is excreted in human breast milk.

    ADVERSE REACTIONS

    Severe

    infection / Delayed / 0-3.0
    elevated hepatic enzymes / Delayed / 1.0-2.0
    anemia / Delayed / 0-2.0
    anorexia / Delayed / 0-1.0
    vomiting / Early / 0-1.0
    diarrhea / Early / 0-1.0
    nausea / Early / 0-1.0
    angioedema / Rapid / 0-1.0
    hepatic failure / Delayed / 0-1.0
    neutropenia / Delayed / 0-1.0
    leukopenia / Delayed / 0-1.0
    asthenia / Delayed / 0-1.0
    fatigue / Early / 0.4-1.0
    thromboembolism / Delayed / 0-1.0
    pulmonary embolism / Delayed / 0-1.0
    rash (unspecified) / Early / 0-1.0

    Moderate

    hot flashes / Early / 5.9-17.7
    constipation / Delayed / 3.5-16.0
    bone pain / Delayed / 7.5-15.8
    dyspnea / Early / 4.4-14.9
    stomatitis / Delayed / 0-13.0
    peripheral edema / Delayed / 9.0-9.0
    chest pain (unspecified) / Early / 0-7.1
    depression / Delayed / 5.7-5.7
    blurred vision / Early / 0-2.0
    hepatitis / Delayed / 0-1.0
    hyperbilirubinemia / Delayed / 0-1.0
    vaginal bleeding / Delayed / 0-1.0
    glossitis / Early / Incidence not known
    oral ulceration / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    neuropathic pain / Delayed / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    cystitis / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known

    Mild

    injection site reaction / Rapid / 7.0-27.0
    headache / Early / 6.7-20.0
    arthralgia / Delayed / 7.8-16.7
    pharyngitis / Delayed / 0-16.1
    back pain / Delayed / 7.5-14.4
    abdominal pain / Early / 0-11.8
    cough / Delayed / 5.3-10.4
    pelvic pain / Delayed / 0-9.9
    myalgia / Early / 0-7.0
    epistaxis / Delayed / 0-7.0
    insomnia / Early / 6.9-6.9
    dizziness / Early / 6.9-6.9
    paresthesias / Delayed / 6.4-6.4
    fever / Early / 5.0-6.4
    alopecia / Delayed / 0-6.0
    xerosis / Delayed / 0-6.0
    musculoskeletal pain / Early / 3.2-5.5
    anxiety / Delayed / 5.0-5.0
    diaphoresis / Early / 0-5.0
    dysgeusia / Early / 0-3.0
    xerophthalmia / Early / 0-2.0
    urticaria / Rapid / 0-1.0
    vertigo / Early / 0-1.0
    lacrimation / Early / 0-1.0
    cheilitis / Delayed / Incidence not known
    rhinitis / Early / Incidence not known
    influenza / Delayed / Incidence not known
    acneiform rash / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known

    DRUG INTERACTIONS

    Anticoagulants: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Antithrombin III: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Apixaban: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Argatroban: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Betrixaban: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Bivalirudin: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Dabigatran: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Dalteparin: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Danaparoid: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Desirudin: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Edoxaban: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Enoxaparin: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Fondaparinux: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Heparin: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Lepirudin: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Pentosan: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Rivaroxaban: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Tinzaparin: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Warfarin: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.

    PREGNANCY AND LACTATION

    Pregnancy

    Although there are no adequate and well-controlled studies in pregnant women, fetal harm or loss may occur if fulvestrant is administered during pregnancy based on animal studies. Females of child-bearing potential should be advised not to become pregnant while receiving fulvestrant or for one year after the last dose. Woman who become pregnant during treatment with fulvestrant should be informed of the potential risk to the fetus. When fulvestrant was administered to pregnant rats and rabbits during organogenesis, embryo-fetal toxicity (including skeletal malformations and fetal loss) occurred at daily doses of 6% and 30% the maximum recommended human dose based on mg/m2, respectively. Fulvestrant, when given prior to and up to implantation, caused embryonic loss in rats at daily doses that were 0.6% of the maximum recommended human dose on a mg/m2 basis; antiestrogenic effects on embryo-fetal development occurred when fulvestrant was administered during organogenesis at 6% of the human recommended dose. Additionally, an increased incidence of fetal abnormalities and fetal loss occurred in rats exposed to fulvestrant at doses equivalent to the human recommended dose on a mg/m2 basis (tarsal flexure of the hind paw at 2 mg/kg/day) as well as much lower doses (non-ossification of the odontoid and ventral tubercle of the first cervical vertebra at >= 0.1 mg/kg/day). Pregnancy loss also occurred in rabbits when fulvestrant was given during organogenesis at doses equivalent to the human dose on a mg/m2 basis. At lower doses (30% of the human dose), fetal malformations included backwards displacement of the pelvic girdle and 27 pre-sacral vertebrae as well as increases in placental weight and post-implantation loss.

    According to the manufacturer, breast-feeding should be discontinued during treatment with fulvestrant and for at least 1 year after the last dose because of the potential for serious adverse reactions in a nursing infant from drug exposure. It is not known if fulvestrant is excreted in human breast milk.

    MECHANISM OF ACTION

    Fulvestrant is a competitive estrogen receptor (ER) antagonist that functions as an estrogen receptor downregulator (ERD). Fulvestrant shows no agonist-type effects in vivo uterotropic assays. In postmenopausal women, the absence of changes in plasma concentrations of FSH and LH in response to fulvestrant treatment suggests no peripheral steroidal effects. Fulvestrant binds to the ER with an affinity comparable to estradiol. Estrogen receptor down-regulation occurs when an antiestrogen acts as an antagonist on the ER, resulting in multiple changes in ER function including impaired dimerization, increased turnover, and disrupted nuclear localization. Fulvestrant also triggers degradation of the ER, causing cellular levels of ER to be markedly reduced.
     
    The transcription of ER-regulated genes is inhibited as a consequence of the down-regulation of ER by fulvestrant. In normal circumstances when estradiol binds to the ER, the following events occur: dissociation of heat shock proteins, ER dimerization, and ER binding to DNA sequences called estrogen response elements (ERE) in the regulatory section of target genes. Two activation domains (AF1 and AF2) are involved in the activation of transcription. As opposed to tamoxifen, which does not inactivate AF1, ERDs such as fulvestrant inactivate both AF1 and AF2. In animal studies, fulvestrant showed no induction of transcription, and when it was administered prior to estradiol or tamoxifen, it completely blocked estrogen or tamoxifen gene induction (e.g., induction of calbindin-D, insulin-like growth factor, vascular endothelial cell growth factor, and c-fos). In postmenopausal women treated with single doses of fulvestrant 15—22 days prior to surgery, there was evidence of increasing down-regulation of ER with increasing dose. The down-regulation of ER was associated with a dose-related decrease in the expression of the progesterone receptor, an estrogen-regulated protein. These effects on ER were also associated with a decrease in cell proliferation (decreased Ki67 labeling index).
     
    In vitro studies demonstrated that fulvestrant is a reversible inhibitor of the growth of tamoxifen-resistant and estrogen-sensitive breast cancer cell lines. Fulvestrant resistant breast tumor xenografts may also be cross-resistant with tamoxifen.

    PHARMACOKINETICS

    Fulvestrant is given by intramuscular injection. Fulvestrant undergoes rapid and extensive distribution. Fulvestrant is highly bound to plasma proteins, primarily VLDL, LDL, and HDL lipoprotein fractions. The role of sex hormone-binding protein could not be determined. Metabolism of fulvestrant is similar to other endogenous corticosteroids and includes oxidation, aromatic hydroxylation, conjugation with glucuronic acid and/or phosphate at the 2, 3, and 17 positions of the steroid nucleus, and oxidation of the sulphoxide side chain. Identified metabolites are either less active or have similar activity as fulvestrant. The hepatic cytochrome P450 (CYP) 3A4 isoenzyme is involved in the oxidation of fulvestrant; however, the importance of the CYP3A4 mechanism in the metabolism of fulvestrant in vivo is unknown. Fulvestrant is rapidly cleared by the hepatobiliary route with excretion primarily via the feces (approximately 90%). Renal elimination is negligible (< 1%).

    Intramuscular Route

    After an intramuscular injection of fulvestrant, plasma concentrations are maximal at about 7 days and are maintained over a period of at least one month. Trough concentrations were about one-third of the Cmax; steady state levels are reached within the first month of dosing.