imatinib (Rx)

Brand and Other Names:Gleevec
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 100mg
  • 400mg

Acute Lymphoblastic Leukemia

Indicated for adults with relapsed or refractory Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL)

600 mg PO qDay

Myelodysplastic/Myeloproliferative Diseases

Diseases associated with platelet-derived growth factor receptor gene re-arrangements as determined with an FDA-approved test

400 mg PO qDay

Hypereosinophilic Syndrome and/or Chronic Eosinophilic Leukemia

Indicated for patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown

With FIP1L1-PDGFRα fusion kinase mutation: 100 mg PO qDay; may increase to 400 mg qDay in absence of adverse drug reactions if assessments demonstrate insufficient response to therapy

FIP1L1-PDGFRα fusion kinase status negative or unknown: 400 mg PO qDay

Chronic Myeloid Leukemia Philadelphia-Chromosome-positive

Indicated for patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) who are newly-diagnosed in chronic phase, or who are in blast crisis, accelerated phase, or chronic phase after interferon-alpha therapy

Chronic phase (newly-diagnosed)

  • 400 mg PO qDay

Chronic phase after failure of interferon-alpha therapy

  • May increase to 600 mg/day in absence of severe adverse drug reaction and severe nonleukemia related neutropenia or thrombocytopenia as follows
    • Disease progression (at any time)
    • Failure to achieve a satisfactory hematologic response after at least 3 months of treatment
    • Failure to achieve a cytogenetic response after 6-12 months of treatment
    • Loss of a previously achieved hematologic or cytogenetic response

Accelerated phase or blast crisis

  • 600 mg PO qDay
  • May increase to 400 mg PO q12hr in absence of severe adverse drug reaction and severe nonleukemia related neutropenia or thrombocytopenia as follows
    • Disease progression (at any time)
    • Failure to achieve a satisfactory hematologic response after at least 3 months of treatment
    • Failure to achieve a cytogenetic response after 6-12 months of treatment
    • Loss of a previously achieved hematologic or cytogenetic response

Dermatofibrosarcoma Protuberans

Indicated for adults with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans

400 mg PO q12hr

Mastocytosis

Indicated for adults with aggressive systemic mastocytosis without the D816V c-Kit mutation as determined with an FDA-approved test or with c-Kit mutational status unknown

Without D816V c-Kit mutation: 400 mg PO qDay

c-Kit mutational status unknown: 400 mg PO qDay if not responding to other therapies

ASM associated with eosinophilia (a clonal hematological disease related to the fusion kinase FIP1L1-PDGFR-alpha): 100 mg PO qDay initially, may increase to 400 mg/day in absence of adverse effects if response to therapy is insufficient

Gastrointestinal Stromal Tumors

Unresectable and/or metastatic malignant GIST

  • 400 mg PO qDay; may increase to 400 mg BID in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions

Adjuvant treatment following complete gross resection of GIST

  • 400 mg PO qDay
  • In clinical trials, 1 and 3 years of imatinib were studied; therefore, recommended duration is 3 years

  • Optimal treatment duration is unknown

Dosage Modifications

Withhold treatment if fluid retention

Hematologic toxicity

  • ASM associated eosinophilia or HES/CEL with FIP1L1-PDGFRα fusion kinase
    • ANC <1000/mm3 and/or platelets <50,000/mm3: Discontinue treatment
    • Resume at dose before reaction when ANC >1500/mm3 and platelets >75,000/mm3
  • Chronic phase CML, MDS/MP, ASM and HES/CEL, GIST
    • Starting dose 400 mg
    • ANC <1000/mm3 and/or platelets <50,000/mm3: Discontinue treatment
    • Resume at original starting dose of 400 mg when ANC >1500/mm3 and platelets >75,000/mm3
    • Recurrence of ANC <1000/mm3 and/or platelets <50,000/mm3: Discontinue treatment; resume at reduced dose of 300 mg/day
  • Accelerated phase and blast crisis Ph+ CML OR Ph+ ALL
    • Starting dose 600 mg
    • ANC <500/mm3 and/or platelets <10,000/mm3: Check if cytopenia is related to leukemia (marrow aspirate or biopsy)
    • If cytopenia is unrelated to leukemia, reduce dose to 400 mg/day
    • If cytopenia persist 2 weeks, reduce further to 300 mg
    • If cytopenia persists 4 weeks and is still unrelated to leukemia, stop imatinib; resume at 300 mg before reaction when ANC ≥1 x 109/L and platelets ≥20 x 109/L
  • DFSP
    • Starting dose 800 mg
    • ANC <1000/mm3 and/or platelets <50,000/mm3: Discontinue treatment
    • Resume at original starting dose of 400 mg when ANC >1500/mm3 and platelets >75,000/mm3
    • Recurrence of ANC <1000/mm3 and/or platelets <50,000/mm3: Discontinue treatment; resume at reduced dose of 400 mg/day

Hepatotoxicity

  • Bilirubin >3x ULN or ALT/AST >5x ULN: Withhold dose; resume after bilirubin <1.5x ULN and ALT/AST <2.5x ULN at a reduced dose (ie, 400 mg to 300 mg; 600 mg to 400 mg; 800 mg to 600 mg)
  • Severe hepatoxicity: Withhold dose; once resolved, resume as appropriate depending on the event

Nonhematologic adverse reactions

  • Severe (eg, severe fluid retention): Withhold; once resolved, resume as appropriate depending on the event

Concomitant strong CYP3A4 inducers

  • Avoid coadministration
  • If strong CYP3A4 inducer must be used, based on pharmacokinetic studies, increase imatinib dose by at least 50%, and monitor clinical response

Hepatic impairment

  • Mild-to-moderate: No dosage adjustment necessary
  • Severe: Reduce dose by 25%

Renal impairment

  • Mild (CrCl 40 to <60 mL/min): Doses >600 mg/day are not recommended
  • Moderate (CrCl 20 to <40 mL/min): Decrease dose by 50%; may increase future doses if tolerated
  • Severe: Use with caution; 100-mg/day dose was tolerated in 2 patients

Pulmonary Arterial Hypertension (Orphan)

Orphan indication sponsor

  • Novartis Drug Regulatory Affairs; East Hanover, NJ 07936-1080

Progressive Multifocal Leukencephalopathy (Orphan)

Orphan designation for treatment of PML

Sponsor

  • Inhibikase Therapeutics, Inc; 3350 Riverwood Parkway, Suite 1927; Atlanta, GA 30339

Dosing Considerations

Monitor

  • CBC qWeek x 4, then q2Weeks x 2, then periodically
  • LFTs at baseline and qMonth
  • Signs of fluid retention

Administration

Take with meal and a large glass of water

For patients unable to swallow, tablets may be dispersed in water or apple juice

Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity

Dosage Forms & Strengths

tablet

  • 100mg
  • 400mg

Chronic Myeloid Leukemia

Indicated for newly diagnosed adult and pediatric patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase

<1 year: Safety and efficacy not established

≥1 year: 340 mg/m²/day PO; not to exceed 600 mg/day  

Acute Lymphoblastic Leukemia

Indicated for treatment of newly diagnosed children with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL)

<1 year: Safety and efficacy not established

≥1 year: 340 mg/m2/day PO; not to exceed 600 mg/day  

Dosage Modifications

Withhold treatment if fluid retention

Hematologic toxicity

  • Pediatric newly diagnosed chronic phase CML
    • Starting dose 340 mg/m2
    • ANC <1000/mm3 and/or platelets <50,000/mm3: Discontinue treatment
    • Resume at previous dose of 400 mg when ANC >1500/mm3 and platelets >75,000/mm3
    • Recurrence of ANC <1000/mm3 and/or platelets <50,000/mm3: Discontinue treatment; resume at reduced dose of 260 mg/m2

Hepatotoxicity

  • Bilirubin >3x ULN or ALT/AST >5x ULN: Withhold dose; resume after bilirubin <1.5x ULN and ALT/AST <2.5x ULN at a reduced dose (ie, 340 mg/m2 to 260 mg/m2)
  • Severe hepatoxicity: Withhold dose; once resolved, resume as appropriate depending on the event

Nonhematologic adverse reactions

  • Severe (eg, severe fluid retention): Withhold; once resolved, resume as appropriate depending on the event

Concomitant strong CYP3A4 inducers

  • Avoid coadministration
  • If strong CYP3A4 inducer must be used, based on pharmacokinetic studies, increase imatinib dose by at least 50%, and monitor clinical response

Hepatic impairment

  • Mild-to-moderate: No dosage adjustment necessary
  • Severe: Reduce dose by 25%

Renal impairment

  • Mild (CrCl 40 to <60 mL/min): Doses >600 mg/day are not recommended
  • Moderate (CrCl 20 to <40 mL/min): Decrease dose by 50%; may increase future doses if tolerated
  • Severe (CrCl <20 mL/min): Use with caution; 100-mg/day dose was tolerated in 2 patients
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Interactions

Interaction Checker

and imatinib

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     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            All grades

            • Decreased hemoglobin (46.9-72.2%)
            • Fluid retention (61.7%)
            • Diarrhea (43.8-59.3%)
            • Periorbital edema (47.2-59.3%)
            • Fatigue (38.8-57%)
            • Nausea (41-53.1%)
            • Rash and related terms (19-40.1%)
            • Decreased WBC count (14.5-34.5%)
            • Musculoskeletal pain (47%)
            • Headache (23-37%)
            • Abdominal pain (14-36.5%)
            • Joint pain (31.4%)
            • Muscle spasms (30.9%)
            • Increased AST (12.2-30.9%)
            • Nasopharyngitis (30.5%)
            • Increased blood creatinine (11.6-30.4%)
            • Dermatitis (29.4%)
            • Increased ALT (16.6-28.9%)
            • Hemorrhage (28.9%)
            • Peripheral edema (26.7%)
            • Pain (25.8%)
            • Decreased neutrophils (16-24.2%)
            • Myalgia (12.2-24.1%)
            • Hypoproteinemia (23.7%)
            • Vomiting (10.8-22.5%)
            • Upper respiratory tract infection (5-21.2%)
            • Cough (20%)
            • Dizziness (4.6-19.4%)
            • Flatulence (8.9-19.1%)
            • Dyspepsia (12-18.9%)
            • Increased lacrimation (9.8-18%)
            • Pharyngeal pain (18.1%)
            • Pyrexia (6.2-17.8%)
            • Anorexia (16.9%)
            • Increased weight (16.9%)
            • Increased weight (13.4-15.6%)
            • Arthralgia (15.1%)
            • Depression (6.8-14.9%)
            • Insomnia (9.8-14.7%)
            • Facial edema (14%)
            • Infection (13.9%)
            • Pruritus (7-12.9%)
            • Constipation (8-12.8%)
            • Dizziness (12.5%)
            • Asthenia (12%)
            • Hypoalbuminemia (11.9%)
            • Sinusitis (11.4%)
            • Alopecia (7-11.3%)
            • Decreased platelets (5-11.3%)
            • Increased bilirubin (11.3%)
            • Bone pain (11.3%)
            • Cough (11%)
            • Increased blood alkaline phosphate (6.5-10.8%)
            • Blurred vision (5-10.8%)
            • Decreased weight (10.1%)

            1-10%

            All grades

            • Hyperglycemia (9.8%)
            • Dysgeusia (6.5-9.3%)
            • Rash (8.9%)
            • Constipation (8.8%)
            • Abdominal distension (7.4%)
            • Back pain (7.4%)
            • Pain in extremity (7.4%)
            • Hypokalemia (7.1%)
            • Facial edema (6.8%)
            • Dry skin (6-6.7%)
            • Upper abdominal pain (2.6-6.2%)
            • Peripheral neuropathy (5.9%)
            • Hypocalcemia (5.6%)
            • Paresthesia (5.2%)
            • Conjunctivitis (5.2%)
            • Palpitations (5.2%)
            • Leukopenia (5%)
            • Stomatitis (5%)
            • Photosensitivity reaction (3.6%)
            • Depression (3.1%)
            • Hemorrhage (3.1%)
            • Nasopharyngitis (1%)

            Grade ≥3

            • Decreased neutrophils (3.3-4.6%)
            • Diarrhea (3-4%)
            • Abdominal pain (3%)
            • Exfoliative rash (2.7%)
            • Increased ALT (2.1-2.7%)
            • Vomiting (2.4%)
            • Nausea (1.5-2.4%)
            • Fatigue (1-2.1%)
            • Dermatitis (2.1%)
            • Increased AST (1.5-2.1%)
            • Infection (1.5%)
            • Periorbital edema (1.2%)
            • Blurred vision (1%)
            • Flatulence (1%)

            <1%

            Grade ≥3

            • Facial edema (<1%)
            • Myalgia (<1%)
            • Arthralgia (<1%)
            • Pain in extremity (<1%)
            • Vomiting (<1%)
            • Hypokalemia (0.9%)
            • Depression (0.9%)
            • Rash (0.9%)
            • Insomnia (0.9%)
            • Stomatitis (0.6%)
            • Back pain (0.6%)
            • Hyperglycemia (0.6%)
            • Pruritus (0.6%)
            • Hemorrhage (0.5%)
            • Dizziness (0.5%)
            • Dyspnea (0.5%)
            • Abdominal distension (0.5%)
            • Peripheral edema (0.5%)
            • Muscle spasms (0.5%)
            • Diarrhea (0.5%)
            • Periorbital edema (0.5%)
            • Decreased hemoglobin (0.5%)
            • Leukopenia (0.3%)
            • Hypocalcemia (0.3%)
            • Upper abdominal pain (0.3%)
            • Facial edema (0.3%)
            • Abdominal distension (0.3%)

            Postmarketing Reports

            Nervous system disorders: Cerebral edema

            Eye disorders: Vitreous hemorrhage

            Cardiac disorders: Pericarditis, cardiac tamponade

            Vascular disorders: Thrombosis/embolism, anaphylactic shock, thrombotic microangiopathy

            Respiratory, thoracic and mediastinal disorders: Acute respiratory failure, interstitial lung disease

            Gastrointestinal disorders: Ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, gastrointestinal perforation, diverticulitis; gastric antral vascular ectasia

            Skin and subcutaneous tissue disorders: Ichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome, drug rash with eosinophilia and systemic symptoms (DRESS)

            Musculoskeletal and connective tissue disorders: Avascular necrosis/hip osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children

            Reproduction disorders: Hemorrhagic corpus luteum/hemorrhagic ovarian cyst

            Hepatitis B virus reactivation

            Renal toxicity

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            Warnings

            Contraindications

            None

            Cautions

            Hypothyroidism reported in patients post-thyroidectomy on levothyroxine replacement; closely monitor TSH levels

            Risk of severe CHF or left ventricular dysfunction, especially in patients with comorbidities; monitor and treat patients with cardiac disease or risk factors for cardiac failure

            In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon initiation of imatinib therapy; reported to be reversible with the administration of systemic steroids, circulatory support measures, and temporarily withholding imatinib

            If anticoagulation required, use LMW or standard heparin instead of warfarin

            Associated with anemia, neutropenia, and thrombocytopenia; CBC counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter

            Sometimes associated with GI irritation; should be taken with food and a large glass of water to minimize this problem; there have been rare reports, including fatalities, of gastrointestinal perforation

            Advise sexually active female patients of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) while in therapy and for 14 days after stopping therapy; if drug is used during pregnancy or if patient becomes pregnant while taking this drug apprise patient of potential hazard to a fetus

            Often associated with edema and occasionally serious fluid retention; probability increases with dose and age >65 yr; investigate unexpected rapid weight gain and provide appropriate treatment

            Bullous dermatologic reactions reported and include erythema multiforme and Stevens-Johnson syndrome

            Severe hepatotoxicity including fatalities may occur; assessAssess liver function before initiation of treatment and monthly thereafter or as clinically indicated; monitor liver function when combined with chemotherapy known to be associated with liver dysfunction

            Grade 3/4 hemorrhage reported in clinical studies in patients with newly diagnosed CML and with GIST; GI tumor sites may be the source of GI bleeds in GIST

            Hypothyroidism reported in thyroidectomy patients undergoing levothyroxine replacement; closely monitor TSH levels in such patients

            Motor vehicle accidents reported with therapy; caution patients about driving a car or operating machinery

            Decline in renal function may occur; evaluate renal function at baseline and during therapy, with attention to risk factors for renal dysfunction

            Drug interaction overview

            • Effects of drugs on imatinib
              • Imatinib is a CYP3A4 substrate
              • CYP3A4 inducers may decrease imatinib plasma concentrations and AUC
              • CYP3A4 inhibitors may increase imatinib plasma concentrations and AUC
            • Effects of imatinib on other drugs
              • Imatinib inhibits CYP3A4 and CYP2D6, which may increase serum concentrations and AUC of CYP3A4 or CYP2D6 substrates
              • Patients who require anticoagulation should receive low-molecular weight or standard heparin instead of warfarin
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            Pregnancy & Lactation

            Pregnancy

            Fetal harm when administered to a pregnant woman based on human and animal data

            No clinical studies available regarding use in pregnant women

            There have been postmarket reports of spontaneous abortions and congenital anomalies from women who have been exposed to imatinib during pregnancy

            Test pregnancy status in females with reproductive potential before initiation of treatment

            Animal data

            • Reproductive studies in rats have demonstrated that imatinib mesylate induced teratogenicity and increased incidence of congenital abnormalities following prenatal exposure to imatinib mesylate at doses equal to the highest recommended human dose of 800 mg/day based on body surface area.
            • Advise women to avoid pregnancy when taking imatinib
            • If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise patient of potential risks to the fetus

            Contraception

            • Females of reproductive potential: Advise to use effective contraception (methods that result in less than 1 % pregnancy rates) during treatment and for 14 days after discontinuing treatment

            Lactation

            Imatinib and its active metabolite are excreted into human milk

            Advise a lactating woman not to breastfeed during treatment and for 1 month after last dose

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Protein-tyrosine kinase inhibitor, specific for abnormal BCR-ABL tyrosine kinase produced by Philadelphia chromosome in CML/ALL

            Absorption

            Bioavailability: 98%

            Peak Plasma Time: 2-4 hr

            Distribution

            Protein Bound: 95%

            Metabolism

            Metabolized mostly by CYP3A4

            Enzymes inhibited: CYP2D6, CYP3A4

            Elimination

            Half-Life: 18 hr (parent drug); 40 hr (metabolite)

            Clearance: 8-14 L/hr

            Excretion: Feces (68%)

            Dialyzable: no

            Pharmacogenomics

            Tyrosine kinase inhibitors (TKIs) inhibit activity of BCR-ABL fusion protein, resulting in both hematologic response (ie, normal cell counts in the peripheral blood and normal bone marrow morphology), as well as cytogenetic response (ie, disappearance or reduction of the Philadelphia [Ph] chromosome)

            NCCN clinical practice guidelines recommends TKIs in CML with confirmed BCR-ABL transcripts in bone marrow or evidence of translocation on cytogenetics

            Genetic testing laboratories

            • The following companies currently offer FISH and/or transcript quantification testing for BCR-ABL
            • Asuragen (http://www.asuragen.com/)
            • Dako (http://www.dakousa.com/)
            • Invitrogen (http://www.invitrogen.com/)
            • Ipsogen (http://www.ipsogen.com)
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            Administration

            Oral Administration

            Take with a meal and a large glass of water

            Patients unable to swallow the film-coated tablets

            • Disperse tablet in a glass of water or apple juice; place tablets in the appropriate volume of beverage (~50 mL for a 100-mg tablet, and 200 mL for a 400-mg tablet) and stirred with a spoon
            • Administer suspension immediately after tablet(s) completely disintegrated

            Storage

            Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF)

            Protect from moisture; do not crush tablets

            Avoid direct contact or exposure to crushed tablets with the skin or mucous membranes

            If such contact occurs, wash thoroughly as outlined in the references

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            Images

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.