Chemotherapeutic Drugs

Question 1

Cyclophosphamide (Cytoxan)

Answer 1

Description

• Most widely-used nitrogen mustard anticancer agent, main uses are for lymphomas, breast cancer, ovarian cancer, lung cancer, bone cancer, neuroblastoma, retinoblastoma, acute and chronic lymphocytic leukemia

Mechanism of action

• Bifunctional alkylating agent; forms DNA-DNA and DNA-protein cross-links
• Prodrug: requires 4-hydroxylation (mostly via CYP2B6) to become cytotoxic
• Tissue selectivity may result from the capacity of normal tissues to degrade the activated intermediates via aldehyde dehydrogenase, glutathione transferase, and other pathways
• A CCNS drug

Pharmacokinetics

• Given PO or IV, Oral F = 0.87-0.96
• PO: 40-180 mg/m2 QD
• IV: varies e.g. 1500-1800 mg/m² in divided doses over 2-5 days; 370-550 mg/m2 Q 7-10 days
• Metabolized by multiple CYPs, 10-20% excreted in the urine unchanged, t1/2 = 3-12 hr

Adverse reactions

• Rapid-onset, potentially fatal heart failure; dysrhythmias, carditis
• Hemorrhagic cystitis: damage to the bladder’s epithelium and blood vessels due to acrolein metabolite

Precautions

• Aggressive hydration (to prevent bladder toxicity)
• Monitor patients with CrCl = 10-24 mL/min for signs of cyclophosphamide toxicity
• Administer 2-mercatpoethanesulfonic acid (MESNA) at 20-40% of the dose for cyclophosphamide doses > 550 mg/m² (protective of hemorrhagic cystitis)
• Hepatic impairment may reduce efficacy

Question 2

Temozolomide (Temodar)

Answer 2

Description

• A DNA-methylaing agent used for glioblastomas, astrocytomas, melanomas

Mechanism of action

• Prodrug, spontaneously hydrolyzed and decarboxylated to a monofunctional DNA alkylating agent; inhibits DNA synthesis and function
• Methylates DNA mainly at N7 (95%) and O6 of guanine residues, anti-tumor activity correlates best with O6 methylation
• A CCNS drug

Pharmacokinetics

• Given PO or IV
• Initial TX is 75 mg/m² daily for 42 days concomitant with focal radiotherapy
• Maintenance phase is usually 150-200 mg/m2 QD for 5 days then 23 days with no drug (6 cycles)
• Good blood-brain barrier permeability

Adverse reactions

• Hepatotoxicity

Precautions

• Perform baseline and periodic LFTs and approximately 2-4 weeks after the last dose

Question 3

Carboplatin (Paraplatin)

Answer 3

Description

• A platinum-based anticancer agent active vs. many solid tumors
• Main uses: cancers of the testes, esophagus and stomach, bladder, lung, ovaries, head, neck

Mechanism of action

• Enter cells by an active Cu++ transporter, CTR1
• The oxylate moiety is displaced by water molecules (aquation) to generate a positively charged and highly reactive molecule that reacts with nucleophilic sites to produce both interstrand and intrastrand DNA cross-links
• N-7 of guanine is a particularly reactive site, leading to platinum cross-links between adjacent guanines (GG intrastrand cross-links)
• A CCNS drug

Pharmacokinetics

• Given by IV infusion over at least 15 min, once every 21-28 days x 6 cycles e.g. 360 mg/m2 Q 4 weeks x 6
• Mostly eliminated by renal excretion within 24 hr as unchanged carboplatin

Adverse reactions

• NV (65%) is less severe than with cisplatin and usually ceases within 24 h of TX; usually responds to antiemetic measures (5-HT3 antagonists, cannabis or Marinol®, D2 antagonists)
• Causes less neurotoxicity, ototoxicity, and nephrotoxicity than cisplatin
• Myelosuppression (mainly thrombocytopenia) is the dose-limiting toxicity

Precautions

• Decrease dose if CrCL < 60 mL/min

Question 4

Bleomycin (Blenoxane)

Answer 4

Description

• Mixture of the two small copper-chelating peptides, bleomycins A2 and B2, isolated from the culture broth of the fungus Streptomyces verticillus
• Main uses: Hodgkin’s disease, non-Hodgkin’s lymphoma, testicular carcinoma, and squamous cell carcinomas of the head, neck, penis, cervix, and vulva

Mechanism of action

• Binds to DNA, generates oxygen free radicals from O2 to cause oxidative damage to the deoxyribose moieties of nucleotides; opens the deoxyribose ring resulting in single- and double-strand DNA breaks
• A CCS drug; causes accumulation of cells in the G2 phase of the cell cycle

Pharmacokinetics

• Administered IV, IM, or SC, or instilled into the bladder for local treatment of bladder cancer; usual dose is 10 to 20 units (~ mg)/m²
• Excreted primarily by the kidneys

Adverse reactions

• Minimally myelo- and immunosuppressive; dose-limiting toxicity is a slowly progressing (weeks) pulmonary toxicity (10%): dyspnea, pneumonitis, fibrosis. Cumulative doses > 250 mg associated with a marked increase in the risk of pulmonary toxicity (pulmonary fibrosis)
• Mucocutaneous reactions (50%): rash, vesiclulation, hyperpigmentation
• Chills, fever (60%)
• Anaphylaxis (1%)

Precautions

• Adjust dose based on CrCL: if CrCL 30-50 mL/min reduce dose by 25%; if CrCL < 30 mL/min reduce dose by 50%
• Pulmonary function tests to monitor for toxicity

Question 5

Doxorubicin (Adriamycin)

Answer 5

Description

• Natural product isolated from the fungus Streptomyces peucetius
• One of the most active single anticancer agents, broad antitumor activity; component of standard combination regimens for breast, lung, GI, liver, and ovarian cancers, lymphomas, others

Mechanism of action

• Intercalates between DNA base pairs, causing the helix to change shape, thereby inhibiting DNA and RNA polymerases
• Stabilizes the DNA-topoisomerase II enzyme complex, inhibits topoisomerase II re-ligation activity, leading to double-strand DNA breaks and apoptosis
• Forms superoxide anion and hydroxyl radicals that damage cell components; stimulated by Fe
• A CCNS drug

Pharmacokinetics

• Administered IV, 40-75 mg/m2 as a single injection Q 21-28 days
• Distributes throughout the body and extensively binds to DNA with levels proportional to the DNA content of the tissue
• Obesity can decrease clearance by ~ 35%

Adverse reactions

• All Pts develop some cardiotoxicity: myocarditis, arrhythmias, abnormal ECG, myocardial damage. Cumulative dose-related toxicity, progresses to CHF (7%); mortality PX with CHF approaches 50%
• Red discoloration of urine and sweat
• Vesicant, severe skin or tissue necrosis if extravasation occurs

Precautions

• Monitor LVEF, DC doxorubicin at the first sign of impaired function
• To reduce risk of cardiotoxicity, do not exceed 550 mg/m2 cumulative dose

Question 6

5-Fluorouracil (5-FU, Efudex)

Answer 6

Description

• Antimetabolite anticancer agent
• Main uses: cancers of the colon, rectum, breast, stomach, and pancreas

Mechanism of action

• Pyrimidine analog, metabolized to fluorodeoxyuridine monophosphate (FdUMP); FdUMP blocks thymidylate synthase, which is required for the conversion of dUMP to TMP → ↓ DNA and RNA synthesis
• Also produces FdUTP which becomes incorporated into both DNA and RNA
• Addition of leucovorin, a folic acid derivative, enhances the toxicity of 5-FU
• A CCS drug

Pharmacokinetics

• Given IV because of low and inconsistent oral bioavailability
• 5-FU is degraded by dihydropyrimidine dehydrogenase, found in liver, intestinal mucosa, tumor cells, and other tissues

Adverse reactions

• Ocular irritation and reversible, excessive lacrimation (50%)
• CV: angina, MI
• GI: NVD, stomatitis, mucositis, mucosal ulceration, anorexia
• DERM: erythema, desquamation, pain, sensitivity to touch on palms and soles (hand-foot syndrome) (erythema w/ white tissue border)
• Myelosuppression

Precautions

• Dihydropyrimidine dehydrogenase (DPD) deficiency (3-8%) → enhanced 5-FU toxicity

Question 7

Gemcitabine (Gemzar)

Answer 7

Description

• Diflurodeoxycytidine antimetabolite anticancer agent
• Main uses: cancers of the GI tract, lung, breast, uterus, ovary, bladder, non-Hodgkin’s lymphoma

Mechanism of action

• Pyrimidine analog, metabolized to mono-, di-, and tri-phosphate nucleotide analogs that inhibit DNA polymerase; dFdCTP is incorporated into DNA to cause strand termination; inhibits replication and repair synthesis metabolism → ↓ DNA and RNA synthesis
• Toxicity not confined to S-phase

Pharmacokinetics

• Administered by IV infusion given over 30 min
• Standard dosing is 1-1.25 g/m2 on days 1, 8, and 15 of each 21- to 28-day cycle, depending on the indication
• Short plasma t1/2 of ~15 min

Adverse reactions

• HEME: myelosuppression
• Flu-like symptoms
• Hepatotoxicity: reversible elevation in LFTs (40%)
• Progressive hemolytic uremic syndrome (rare)

Precautions

• Potent radiosensitizer; not used with radiotherapy except in closely monitored clinical trials

Question 8

Methotrexate (MTX; Trexall)

Answer 8

Description

• Antimetabolite anticancer agent
• Main uses: leukemias, lymphomas, cancers of the head, neck, lung, and breast
• Immunosuppressive, widely used for rheumatoid arthritis and psoriasis

Mechanism of action

• Folic acid analog, high-affinity active site inhibitor of DHFR (dihydrofolate reductase) → depletion of the reduced folates required for the biosynthesis of dTTP and purines → ↓ DNA, RNA, protein synthesis
• Also converted to MTX-polyglutamates which accumulate and inhibit TS and other enzymes
• A CCS drug

Pharmacokinetics

• Given PO and IV
• For rheumatoid arthritis, 7.5 mg PO Q week, for psoriasis, 10-25 mg PO or IV Q week
• Renal excretion is the primary route of elimination, occurs by glomerular filtration and active tubular secretion (exceeds GFR)

Adverse reactions (dose- and frequency-dependent)

• GI: stomatitis, esophagitis, oral ulceration
• DERM: toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis
• Impaired wound healing
• Myelosuppression
• Pneumonitis
• Hepatotoxicity
• Renal toxicity

Precautions

• NSAIDs reported to reduce the tubular secretion of MTX and may enhance its toxicity

Question 9

Vincristine (Oncovin)

Answer 9

Description

• Spindle poison anticancer agent
• Vinca alkaloid from Catharanthus rosea (periwinkle plant)
• Main uses: solid tumors, lymphomas, leukemias, rhabdomyosarcoma, neuroblastoma and other brain tumors, nephroblastoma

Mechanism of action

• Binds to tubulin, (prevents polymerization) disrupting microtubule assembly and mitotic spindle formation → inhibits cell division, cell division arrests in M phase
• A CCS drug

Pharmacokinetics

• Administered IV, commonly 1.4-2 mg/m2 at weekly or longer intervals
• Elimination half-life is between 23-85 hr

Adverse reactions

• Neurotoxicity is the dose-limiting adverse effect, manifested as paresthesia and tingling that occurs in a “stocking-and-glove” pattern, cranial nerve damage, paralysis, ANS dysfunction (orthostatic hypotension, urinary retention, and paralytic ileus or constipation)
• Reversible alopecia, frequently without cessation of therapy
• Limited myelosuppression

Precautions

• Intrathecal or cisternal administration of vincristine is uniformly fatal; immediate intervention is required in order to prevent ascending muscle paralysis leading to death

Question 10

Paclitaxel (Taxol)

Answer 10

Description

• Spindle poison anticancer agent
• Derivative from the bark of the Pacific yew tree, Taxus brevifolia
• Main uses: ovarian, breast, lung, GI, urogenital, head, and neck cancers

Mechanism of action

• Promotes polymerization and assembly of microtubules, making them extremely stable and nonfunctional → inhibits cell division, cell division **arrests in M phase ** (cannot depolymerize)
• A CCS drug

Pharmacokinetics

• Administered IV in a vehicle of 50% EtOH and 50% polyethoxylated castor oil; vehicle is likely responsible for a high rate of hypersensitivity reactions
• Administered as a 3 hr infusion of 135-175 mg/m2 Q 3 weeks or as a 1 hour infusion of 80-100 mg/m2 Q week
• Extensive hepatic metabolism, mostly by CYP2C8, also CYP3A4
• Approximately 70-80% of the dose is eliminated in the feces within 1 week

Adverse reactions

• “Stocking-and-glove” peripheral neuropathy (62%)
• Myelosuppression
• Asymptomatic abnormalities in the ECG (33%), bradycardia
• Mucositis

Precautions

• Pretreat with H1 antagonist (e.g. diphenhydramine), H2 antagonist (e.g. ranitidine), and a glucocorticoid (e.g. dexamethasone) to reduce likelihood of hypersensitivity reaction
• Heart disease (angina, arrhythmias, CHF, MI within the past 6 months)
• Dose reductions in patients with abnormal hepatic function or hepatic metastases > 2 cm in size

Question 11

Etoposide (VePesid)

Answer 11

Description

• Semisynthetic drug derived from the resin of the Podophyllum peltatum (mandrake root or May apple)
• Main uses: lung and testicular cancers, also lymphomas, nonlymphocytic leukemia, Kaposi sarcoma

Mechanism of action

• Forms ternary complex with DNA and topoisomerase II, an enzyme that coils and uncoils DNA; stabilizes DNA-topoisomerase II complex, prevents religation of double-strand breaks induced by topoisomerase II; strand breaks accumulate and progression in the cell cycle is stopped; cell undergoes apoptosis
• A CCS drug, mainly active in S and G2

Pharmacokinetics

• Administered by IV infusion over 30-60 min, usual range is 35-100 mg/m2 for 4-5 days, cycles are repeated Q 3-4 weeks; PO form is available, dose is twice the IV dose
• 97% bound to serum albumin; toxicity correlates with hepatic health
• ~ 56% excreted in the urine and 44% excreted in the feces after 5 days

Adverse reactions

• Dose-limiting toxicity is leukopenia
• NVD and stomatitis (15%)
• Reversible alopecia

Precautions

• Adjustments for renal impairment: if CrCL 45-60 mL/min, reduce dose by 15%; if CrCL 30-44 mL/min, reduce dose by 20%; if CrCL < 30 mL/min, reduce dose by 25%
• Hepatic disease

Question 12

Irinotecan (Camptosar)

Answer 12

Description

• Derived from a plant alkaloid isolated from the Chinese tree Camptotheca acuminata
• Main uses: colorectal, ovarian, lung cancers; also pancreatic cancer, refractory lymphoma, malignant gliomas

Mechanism of action

• Prodrug, requires cleavage by hepatic carboxylesterases to the active metabolite
• Binds to and stabilizes the normally transient DNA-topoisomerase I cleavable complex, leading to the accumulation of single-stranded DNA breaks; collision of a DNA replication fork with this opened strand of DNA causes an irreversible double-strand DNA break, ultimately leading to cell death
• A CCS drug; ongoing DNA synthesis is required for cytotoxicity, thus irinotecan is S phase-specific

Pharmacokinetics

• Given by 90 min IV infusion at 125 mg/m2 weekly (on days 1, 8, 15, and 22) for 4 out of 6 weeks, or at 350 mg/m2 Q 3 weeks
• Metabolized by hepatic CYPs that are induced by antiseizure drugs

Adverse reactions

• Dose-limiting toxicity is delayed diarrhea (35%, usually resolves within a week), with or without neutropenia
• Myelosuppression (14-47%)
• PNS: cholinergic syndrome from inhibition of AChE; short lasting and responds to atropine
• UG: hemorrhagic cystitis

Precautions

• Individuals homozygous for the UGT1A1*28 allele (UGT1A1 7/7 genotype) are at increased risk for neutropenia; testing advised
• Hepatic status

Question 13

Bevacizumab (Avastin)

Answer 13

Description

• Recombinant humanized monoclonal IgG1 antibody produced in a Chinese hamster ovary (CHO) cell expression system
• First anti-angiogenesis agent to show efficacy in treating cancer in patients
• Main uses: colorectal, non-small cell lung, breast, and kidney cancers, glioblastomas

Mechanism of action

• Vascular endothelial growth factor inhibitor, binds to VEGF-A, prevents VEGF-A from interacting with the target VEGF receptors, thereby inhibiting angiogenesis
• Inhibits cell growth, induces apoptosis
• A CCNS drug

Pharmacokinetics

• Administered as IV infusion over 30-90 min at 5-15 mg/kg Q 2-3 weeks
• Mean t1/2 ~ 20 days

Adverse reactions

• CV: hypertension, increased arterial thromboembolic events (transient ischemic attack, stroke, angina, MI)
• Impaired wound healing
• GI perforations, pain, nausea
• Proteinuria
• Infusion reactions: headache, fever, rash

Precautions

• Monitor blood pressure Q 2-3 weeks during treatment
• Suspend drug administration for ≥ 2 g proteinuria/24 hr, resume when proteinuria is < 2 g/24 hr

Question 14

Cetuximab (Erbitux)

Answer 14

Description

• Genetically engineered human-mouse fusion IgG1 antibody directed against the EGF receptor
• TX of EGFR-expressing metastatic colorectal, head, and neck cancers

Mechanism of action

• Binds to the extracellular domain of the human epidermal growth factor receptor (EGFR) to inhibit EGFR-dependent signaling
• Inhibits cell growth, induces apoptosis, induces antibody-dependent cellular toxicity
• A CCNS drug

Pharmacokinetics

• Given by IV infusion over 60-120 min, loading dose of 400 mg/m2, followed by weekly IV doses of 250 mg/m2
• Mean t1/2 = 7.5 days

Adverse reactions

• Infusion reaction to mouse antigen (19%) (allergic rxn): fever, chills, NV, hypotension, angioedema, bronchospasm
• DERM (90%) acneiform rash, dry skin, fissures, pruritus, exfoliation

Precautions

• Monitor for 1 hr after infusion for anaphylactic reaction, treat with epinephrine, corticosteroids, IV antihistamines, bronchodilators, and oxygen as needed

Question 15

Rituximab (Rituxan)

Answer 15

Description

• Genetically engineered human-mouse fusion IgG1 antibody produced in CHO cells
• First monoclonal antibody to be used as a chemotherapeutic agent
• TX of relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL)
• Commonly used as an adjunct in combination regimens

Mechanism of action

• Binds specifically to CD20, a B-lymphocyte antigen; CD20 antigen is expressed on > 90% of B-cells in NHL
• Promotes lysis of B-cells by cytotoxic immune cells (antibody-dependent cellular toxicity)
• A CCNS drug

Pharmacokinetics

• Administered as IV infusion over 90 min at 375 mg/m², usually given weekly for 4-8 weeks
• Median time to onset of response is ~ 50 days, and the median duration of response is 10-12 months
• Upon completion of a TX course, rituximab can be detected in a patient’s serum for about 3-6 months

Adverse reactions

• Severe or life-threatening events in 57% of patients: CV, GI, renal toxicity
• Infusion reaction to mouse antigen (80%): fever, chills, NV, hypotension, angioedema, bronchospasm
• Infections (31%)
• Mucocutaneous reactions: rash, vesiclulation, exfoliative dermatitis

Precautions

• All patients should receive diphenhydramine, acetaminophen, and possibly corticosteroids as premedication for rituximab infusions

Question 16

Trastuzumab (Herceptin)

Answer 16

Description

• Genetically engineered humanized monoclonal antibody against human epidermal growth factor receptor (HER2/neu)
• HER2/neu is overexpressed in 30% of breast cancers, PX candidates are screened for this phenotype
• First monoclonal antibody to be approved for the treatment of a solid tumor

Mechanism of action

• Binds to the external domain of HER2/neu tyrosine kinase receptor to prevent receptor activation by EGF; decreases downstream signals, metastatic potential, and promotes apoptosis
• Induces antibody-dependent cellular toxicity
• A CCNS drug

Pharmacokinetics

• Given as IV infusion over 30-90 min at 2-6 mg/kg, usually given weekly for 12-18 weeks
• Mean t1/2 = 6-16 days

Adverse reactions

• Infusion reactions: fever, chills, nausea, dyspnea, rashes
• CV: potentially fatal ventricular dysfunction, CHF
• Discontinuation may be necessary

Precautions

• Assess LVEF prior to and during TX

Question 17

Temsirolimus (Torisel)

Answer 17

Description

• Macrocyclic lactone produced by Streptomyces hygroscopicus
• Approved for advanced renal cancer

Mechanism of action

• Binds to FKBP, complex then binds to and inhibits mTOR, a key kinase involved in upstream regulation of protein synthesis, cell growth, proliferation; inhibits progression from G1 to S phase of the cell cycle

Pharmacokinetics

• 25 mg is diluted in NS and given by weekly 30-60 min IV infusion
• Metabolized to sirolimus and other metabolites by CYP3A4 (→ drug interactions!) and eliminated mainly in the feces
• Temsirolimus has a t1/2 ~ 30 hr, sirolimus has t1/2 ~ 60 hr

Adverse reactions (similar to sirolimus)

• PULM: dyspnea (28%), pharyngitis (12%)
• HEME: myelosuppression (19-53%)
• GI: mucositis (41%) NVD (19-37%)
• MET (83-87%): hyperlipidemia, hypertriglyceridemia, edema (35%)
• DERM: rash (47%), pruritus (19%), dry skin (11%)
• Hypersensitivity/infusion reactions

Precautions

• PX should receive prophylactic diphenhydramine or similar antihistamine IV (25-50 mg) 30 min before TX

Question 18

Erlotinib (Tarceva)

Answer 18

Description

• Oral, selective epidermal growth factor receptor (EGFR) inhibitor
• Main uses: non-small cell lung cancer, pancreatic cancer
• Other uses under investigation include colorectal cancer and cancers of the head and neck, genitourinary tract, stomach, liver, kidney, breast, and mesothelioma

Mechanism of action

• tyrosine kinase inhibitor

- Reversible inhibitor of EGFR; binds to ATP binding pocket in the receptor tyrosine kinase domain of the EGFR, prevents autophosphorylation of receptor following EGF binding and receptor dimerization

• Clinical effect is a decrease in cellular growth and proliferation, especially EGF-dependent cancer cells

Pharmacokinetics

• Usual dose is 100-150 mg QD PO
• Metabolized mainly by hepatic CYP3A4 (→ drug interactions!) and eliminated in feces (83%)
• t1/2 ~ 36 hr

Adverse reactions

• Rash (60-85%), diarrhea (20-62%), anorexia (52%), and fatigue (52%) are the most common adverse effects

Precautions

• Periodic LFTs

Question 19

Imatinib (Gleevec)

Answer 19

Description

• Tyrosine kinase inhibitor; first molecularly targeted protein kinase inhibitor to receive FDA approval
• Main uses: chronic myelogenous leukemia (CML), GI stromal cell tumors (GIST), or cancers in with certain tyrosine kinases are constitutively active (c-kit, PDGF, others)

Mechanism of action

• Targets constitutively active BCR-Abl tyrosine kinase receptor created by the “Philadelphia” chromosome 9:22 translocation; also targets other tyrosine receptor kinases
• Competitive inhibitor of ATP binding domain, prevents binding and hydrolysis of ATP, effectively blocking BCR-Abl and other tyrosine kinase-mediated substrate phosphorylation
• Clinical effect is a decrease in cell growth and proliferation

Pharmacokinetics

• Standard dose is 400-600 mg QD PO
• Metabolized mainly by hepatic CYP3A4 (→ drug interactions!); e.g. a single dose of ketoconazole increases the maximal [imatinib] in plasma and its plasma AUC by 26% and 40%, respectively
• t1/2 of imatinib and its major active metabolite, the N-desmethyl derivative, are ~ 18 and 40 hr, respectively

Adverse reactions

• NVD (22-50%), elevated LFTs (2-4%), edema (60%), myelosuppression (13%)

Precautions

• Monitor LFTs
• Imatinib should be taken with food and water to minimize GI distress

Question 20

Sunitinib (Sutent)

Answer 20

Description

• Orally active multiple tyrosine kinase inhibitor
• Main uses: Renal cell cancers, GI stromal cell tumors (GIST), pancreatic neuroendocrine tumors

Mechanism of action

• Competitive inhibitor of ATP binding domain in tyrosine kinases, prevents binding and hydrolysis of ATP
• Inhibitor of multiple receptor tyrosine kinases including PDGF receptors, VEGF receptors, stem cell factor receptor and others which are involved in tumor growth and metastasis
• Clinical response is inhibition of angiogenesis, invasion, and metastasis

Pharmacokinetics

• Usually given as 50 mg QD PO 4 weeks, followed by 2 weeks with no drug
• Metabolized mainly by hepatic CYP3A4 (→ drug interactions!)

Adverse reactions

• Hypertension, ND, rash or other skin changes (yellow discoloration in ~ 33% of patients), hypothyroidism (40-60%) stomatitis, fatigue (50-70%), cardiac dysfunction, neutropenia (10%)

Precautions

• Monitor LFTs
• Baseline and periodic evaluations of LVEF