Cobimetinib (Monograph)

Brand name: Cotellic
Drug class: Antineoplastic Agents
- Mitogen-activated Extracellular Signal-regulated Kinase Inhibitor
- MEK Inhibitor
Chemical name: (2E)-2-Butenedioate (2:1) [3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl][3-hydroxy-3-(2S)-2-piperidinyl-1-azetidinyl]-methanone
Molecular formula: 2(C₂₁H₂₁F₃IN₃O₂)•C₄H₄O₄
CAS number: 1369665-02-0

Medically reviewed by Drugs.com on Dec 13, 2021. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK2.

Uses for Cobimetinib

Melanoma

In combination with vemurafenib for treatment of unresectable or metastatic melanoma with b-Raf serine-threonine kinase (BRAF) V600E or V600K mutation (designated an orphan drug by FDA for this use).

FDA-approved in vitro diagnostic test (e.g., cobas 4800 BRAF V600 mutation test) required to confirm presence of BRAF V600E or V600K mutation prior to initiation of therapy.

Limited data suggest greater efficacy (longer progression-free and overall survival, higher objective response rates) in patients with BRAF inhibitor-naive disease versus those with disease progression during prior BRAF inhibitor therapy.

Cobimetinib Dosage and Administration

General

Pretreatment Screening

Confirm presence of b-Raf serine-threonine kinase (BRAF) V600E or V600K mutation prior to initiation of combination therapy with cobimetinib and vemurafenib.
Dermatologic evaluation.
LVEF.
Liver function tests.
Serum CK and S_cr concentrations.

Patient Monitoring

Dermatologic evaluation every 2 months during therapy. Continue monitoring for 6 months following discontinuance of cobimetinib and vemurafenib.
Monitor for new noncutaneous malignancies during combination therapy with cobimetinib and vemurafenib.
Assess LVEF 1 month after initiation of cobimetinib therapy and then every 3 months during therapy.
Perform ophthalmologic examinations regularly and as clinically indicated (i.e., if new or worsening visual disturbances occur) during cobimetinib therapy.
Perform liver function tests monthly or more frequently as clinically indicated, during therapy.
Evaluate serum CK and creatinine concentrations periodically and as clinically indicated, during therapy.

Other General Considerations

Avoid exposure to sunlight during therapy.
When used in combination with vemurafenib, the usual cautions, precautions, and contraindications associated with vemurafenib must be considered in addition to those associated with cobimetinib.

Administration

Oral Administration

Administer orally once daily without regard to meals.

Dosage

Available as cobimetinib fumarate; dosage expressed in terms of cobimetinib.

Adults

Melanoma

Oral

60 mg once daily on days 1–21 of each 28-day cycle; use in combination with vemurafenib. Continue therapy until disease progression or unacceptable toxicity occurs.

Avoid concomitant use with potent or moderate inhibitors of CYP3A; if concomitant short-term use of a moderate CYP3A inhibitor cannot be avoided, reduce cobimetinib dosage from 60 mg once daily to 20 mg once daily. (See Interactions.)

Dosage Modification for Toxicity

Oral

Adjust dosage in decrements of 20 mg daily.

Dosages <20 mg once daily not recommended; permanently discontinue drug if 20-mg daily dosage is not tolerated.

Hemorrhage

Oral

If grade 3 hemorrhage occurs, interrupt cobimetinib therapy for up to 4 weeks until toxicity improves to grade 1 or less, and then resume at a reduced dosage. If toxicity does not improve within 4 weeks of withholding cobimetinib, permanently discontinue drug.

If grade 4 hemorrhage occurs, permanently discontinue drug.

Cardiovascular Toxicity

Oral

If asymptomatic absolute decrease in left ventricular ejection fraction (LVEF) from baseline of >10% and to a level below lower limit of normal (LLN) occurs, interrupt cobimetinib therapy for 2 weeks and reassess LVEF. When LVEF recovers to at least the LLN and absolute decrease from baseline is ≤10%, resume cobimetinib at a reduced dosage. (See Cardiac Effects under Cautions.)

If symptomatic decrease in LVEF from baseline occurs, interrupt cobimetinib therapy for up to 4 weeks and reassess LVEF. When symptoms resolve, LVEF recovers to at least the LLN, and absolute decrease in LVEF from baseline is ≤10%, resume cobimetinib at a reduced dosage.

If LVEF remains below the LLN, absolute decrease in LVEF from baseline remains >10%, or symptoms persist, permanently discontinue drug.

If QT-interval prolongation occurs during combination therapy with cobimetinib and vemurafenib, dosage modification for vemurafenib may be required. Dosage adjustment for cobimetinib not necessary.

Dermatologic Effects

Oral

If intolerable grade 2 dermatologic reactions or grade 3 or 4 dermatologic reactions occur, interrupt cobimetinib therapy or reduce dosage.

Ocular Effects

Oral

If serous retinopathy occurs, interrupt cobimetinib therapy for up to 4 weeks until visual manifestations improve, and then resume at a reduced dosage. If toxicity does not improve or if symptoms recur within 4 weeks of resuming therapy at a reduced dosage, permanently discontinue drug.

If retinal vein occlusion occurs, permanently discontinue drug.

Hepatotoxicity

Oral

For first occurrence of grade 4 liver function test abnormalities, interrupt cobimetinib therapy for up to 4 weeks until toxicity improves to grade 1 or less, and then resume at a reduced dosage. If liver function test abnormalities do not improve within 4 weeks of interrupting therapy, permanently discontinue drug.

If grade 4 liver function test abnormalities recur, permanently discontinue drug.

Musculoskeletal Effects

Oral

In patients with grade 4 elevations in CK concentration or any grade of CK elevation with concomitant myalgia, interrupt cobimetinib therapy for up to 4 weeks until toxicity improves to grade 3 or less, and then resume at a reduced dosage. If toxicity does not improve within 4 weeks of interrupting therapy, permanently discontinue drug.

Photosensitivity Reactions

Oral

If intolerable grade 2 photosensitivity or grade 3 or 4 photosensitivity occurs, interrupt cobimetinib therapy for up to 4 weeks until toxicity improves to grade 1 or less, and then resume at a reduced dosage. If toxicity does not improve within 4 weeks of interrupting therapy, permanently discontinue drug.

Development of New Primary Malignancies

Oral

No dosage adjustment necessary.

Other Toxicity

Oral

If intolerable grade 2 or any grade 3 adverse reaction occurs, interrupt cobimetinib therapy for up to 4 weeks until toxicity improves to grade 1 or less, and then resume at a reduced dosage. If toxicity does not improve within 4 weeks of interrupting therapy, permanently discontinue drug.

For first occurrence of any grade 4 adverse reaction, permanently discontinue drug or interrupt cobimetinib therapy until toxicity improves to grade 1 or less and then resume at a reduced dosage. If grade 4 adverse reaction recurs, permanently discontinue drug.

Prescribing Limits

Adults

Melanoma

Oral

Dosages <20 mg once daily not recommended.

Special Populations

Hepatic Impairment

Mild, moderate, or severe preexisting hepatic impairment (Child-Pugh class A, B, or C): No dosage adjustment required. (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild (Cl_cr 60–89 mL/minute) or moderate (Cl_cr 30–59 mL/minute) renal impairment: No dosage adjustment required.

Severe renal impairment: Appropriate dosage not established.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Cobimetinib

Contraindications

Manufacturer states none known.

Warnings/Precautions

Sensitivity Reactions

Photosensitivity Reactions

Photosensitivity reactions, sometimes severe, reported.

Avoid exposure to sunlight during cobimetinib therapy. (See Advice to Patients.) If photosensitivity reactions occur, interrupt therapy, reduce dosage, or permanently discontinue drug. (See Dosage Modification under Dosage and Administration.)

Combination Therapy

When used in combination with vemurafenib, consider cautions, precautions, and contraindications of vemurafenib.

Development of New Primary Malignancies

Cutaneous squamous cell carcinoma, keratoacanthoma, basal cell carcinoma, and new primary melanoma reported. Median time to detection of cutaneous squamous cell carcinoma, keratoacanthoma, or basal cell carcinoma was 4 months after initiating combination therapy with cobimetinib and vemurafenib in the coBRIM study in patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation. New primary melanoma reported in 2 patients at 9 and 12 months after initiation of combination therapy with cobimetinib and vemurafenib.

Noncutaneous malignancies reported in 0.8% of patients receiving cobimetinib in combination with vemurafenib compared with 1.2% of those receiving vemurafenib alone.

Perform dermatologic evaluation at baseline and every 2 months during therapy; continue monitoring for 6 months following discontinuance of cobimetinib and vemurafenib. Initiate appropriate therapy and excise suspicious cutaneous lesions for pathologic evaluation.

Monitor for new noncutaneous malignancies.

Hemorrhage

Hemorrhage, including major hemorrhagic events (i.e., symptomatic bleeding in a critical area or organ), reported. Increased incidence of GI hemorrhage, reproductive system hemorrhage, or hematuria observed during combination therapy with cobimetinib and vemurafenib compared with vemurafenib alone. Cerebral hemorrhage reported in 2 patients receiving combination therapy compared with none of those receiving vemurafenib alone.

If hemorrhagic events occur, interrupt therapy, reduce dosage, or permanently discontinue drug. (See Dosage Modification under Dosage and Administration.)

Cardiac Effects

Cardiomyopathy (i.e., symptomatic or asymptomatic decrease in LVEF), sometimes requiring temporary interruption, dosage modification, or permanent discontinuance of therapy, reported. Median time to first onset of left ventricular dysfunction was 4 months in the coBRIM study. Left ventricular dysfunction resolved (i.e., LVEF exceeded LLN or was within 10% of baseline) in most patients; median time to resolution was 3 months.

Safety not established in patients with baseline LVEF below the LLN or <50%.

Assess LVEF prior to and 1 month after initiation of therapy, then every 2–3 months during therapy. If left ventricular dysfunction occurs, interrupt therapy, reduce dosage, or permanently discontinue drug. (See Dosage Modification under Dosage and Administration.) Reassess LVEF approximately 2, 4, 10, and 16 weeks following reinitiation of the drug and then as clinically indicated.

Dermatologic Effects

Severe dermatologic reactions, sometimes requiring hospitalization, reported. Median time to onset of grade 3 or 4 rash in patients receiving combination therapy with cobimetinib and vemurafenib was 11 days in the coBRIM study. Grade 3 or 4 rash resolved completely in most patients; median time to resolution was 21 days.

If dermatologic reactions occur, interrupt therapy, reduce dosage, or permanently discontinue drug. (See Dosage Modification under Dosage and Administration.)

Ocular Effects

Ocular toxicities (e.g., serous retinopathy, retinal vein occlusion) reported. Serous retinopathy usually occurred 2 days to 9 months following initiation of therapy. Duration ranged from 1 day to 15 months.

Perform ophthalmologic examinations regularly and as clinically indicated (i.e., if new or worsening visual disturbances occur) during therapy. If ocular toxicities occur, interrupt therapy, reduce dosage, or permanently discontinue drug. (See Dosage Modification under Dosage and Administration.)

Hepatic Toxicity

Liver function test abnormalities reported.

Perform liver function tests prior to initiation of therapy and then monthly, or more frequently as clinically indicated. If liver function test abnormalities occur, interrupt therapy, reduce dosage, or permanently discontinue drug. (See Dosage Modification under Dosage and Administration.)

Musculoskeletal Effects

Rhabdomyolysis reported. Median time to first occurrence of grade 3 or 4 CK elevations was 16 days in patients receiving combination therapy with cobimetinib and vemurafenib in the coBRIM study; median time to complete resolution was 15 days.

Evaluate serum CK and S_cr concentrations at baseline, periodically during therapy, and as clinically indicated. If elevated CK concentrations occur, evaluate for manifestations of rhabdomyolysis and for other potential causes. If increased CK concentrations occur, interrupt therapy, reduce dosage, or permanently discontinue drug. (See Dosage Modification under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Embryotoxicity and teratogenicity demonstrated in animals.

Pregnancy should be avoided during cobimetinib therapy and for ≥2 weeks after drug discontinuance. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard. (See Advice to Patients.)

Impairment of Fertility

May impair female and male fertility.

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether cobimetinib is distributed into milk. Discontinue nursing during therapy and for 2 weeks after drug discontinuance.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.

Hepatic Impairment

Hepatic impairment does not substantially affect systemic exposure of cobimetinib; dosage adjustment not necessary in such patients. (See Special Populations under Pharmacokinetics.)

Renal Impairment

Formal pharmacokinetic studies not conducted in patients with renal impairment.

In a population pharmacokinetic analysis, systemic exposure not altered by mild or moderate renal impairment; dosage adjustment not necessary in such patients. (See Special Populations under Pharmacokinetics.)

Not studied in patients with severe renal impairment.

Common Adverse Effects

Adverse effects reported in ≥10% of patients receiving cobimetinib in combination with vemurafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutation and at an incidence that is at least 5% higher than that reported with vemurafenib alone include diarrhea, photosensitivity reaction, nausea, pyrexia, vomiting, acneiform rash, hypertension, vision impairment, stomatitis, chorioretinopathy, hemorrhage, retinal detachment, chills, and arthralgia.

Laboratory abnormalities reported in >10% of patients receiving cobimetinib in combination with vemurafenib include elevated concentrations of serum creatinine, elevated concentrations of CK, elevated concentrations of aminotransferases (i.e., AST, ALT), lymphopenia, elevated concentrations of alkaline phosphatase, anemia, hypophosphatemia, elevated concentrations of γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP), hypoalbuminemia, hyponatremia, hyperkalemia, hypokalemia, hypocalcemia, and thrombocytopenia.

Interactions for Cobimetinib

Principally metabolized by CYP3A and UGT2B7.

Substrate of CYP3A. May inhibit CYP isoenzymes 3A and 2D6. At clinically relevant concentrations, does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, and 2C19 or induce CYP isoenzymes 1A2, 2B6, and 3A4.

Substrate of P-glycoprotein (P-gp). Does not inhibit P-gp at clinically relevant concentrations.

In vitro, neither a substrate nor inhibitor of breast cancer resistance protein (BCRP), organic cation transporter (OCT) 1, OCT2, organic anion transport protein (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, and OAT3 at clinically relevant concentrations.

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible increased systemic exposure of cobimetinib. Avoid concomitant use. (See Specific Drugs and Foods under Interactions.)

Moderate CYP3A inhibitors: Possible increased systemic exposure of cobimetinib. Simulations suggest that administration of cobimetinib 20 mg once daily with a moderate CYP3A inhibitor for <14 days results in steady-state concentrations similar to those achieved with cobimetinib 60 mg once daily alone. Avoid concomitant use. (See Specific Drugs and Foods under Interactions.) If concomitant short-term therapy (≤14 days) with a moderate CYP3A inhibitor cannot be avoided, reduce cobimetinib dosage from 60 mg once daily to 20 mg once daily; when the moderate CYP3A inhibitor is discontinued, resume prior cobimetinib dosage of 60 mg once daily. In patients receiving a reduced cobimetinib dosage (40 or 20 mg once daily), select alternative drug with no or mild CYP3A inhibitory activity.

Moderate or potent CYP3A inducers: Possible decreased systemic exposure and reduced efficacy of cobimetinib. Simulations suggest that concomitant use of a potent or moderate CYP3A inducer may decrease cobimetinib exposure by 83 or 73%, respectively. Avoid concomitant use. (See Specific Drugs and Foods under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2D6: Pharmacokinetic interaction not observed to date.

Substrates of CYP3A: Pharmacokinetic interaction not observed to date.

Drugs Affecting Efflux Transport Systems

Inhibitors of P-gp: Possible increased concentrations of cobimetinib.

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Amiodarone	Possible increased cobimetinib exposure	Avoid concomitant use
Anticonvulsants (e.g., carbamazepine, phenytoin)	Moderate or potent CYP3A inducers: Possible decreased systemic exposure and reduced efficacy of cobimetinib	Moderate or potent CYP3A inducers: Avoid concomitant use
Antifungals, azoles (e.g., fluconazole, itraconazole, posaconazole, voriconazole)	Moderate or potent CYP3A inhibitors: Possible increased cobimetinib exposure Itraconazole: Increased cobimetinib AUC (by 6.7-fold) and peak concentrations (by 3.2-fold)	Moderate or potent CYP3A inhibitors: Avoid concomitant use If short-term (≤14 days) use of an antifungal with moderate CYP3A inhibitory activity (e.g., fluconazole) cannot be avoided, reduce cobimetinib dosage from 60 mg once daily to 20 mg once daily, then resume 60-mg daily dosage when the antifungal is discontinued; select alternative antifungal with no or mild CYP3A inhibitory activity if cobimetinib dosage is already reduced (40 or 20 mg once daily)
Antimycobacterials, rifamycins (e.g., rifampin)	Possible decreased systemic exposure and reduced efficacy of cobimetinib	Avoid concomitant use
Antiretroviral agents, HIV protease inhibitors (e.g., fosamprenavir, lopinavir, ritonavir)	Moderate or potent CYP3A inhibitors: Possible increased cobimetinib exposure	Moderate or potent CYP3A inhibitors: Avoid concomitant use
Antiretroviral agents, nonnucleoside reverse transcriptase inhibitors (e.g., efavirenz)	Moderate or potent CYP3A inducers: Possible decreased systemic exposure and reduced efficacy of cobimetinib	Moderate or potent CYP3A inducers: Avoid concomitant use
Calcium-channel blocking agents, nondihydropyridine (diltiazem, verapamil)	Diltiazem, verapamil: Possible increased cobimetinib exposure	Diltiazem, verapamil: Avoid concomitant use
Ciprofloxacin	Possible increased cobimetinib exposure	Avoid concomitant use If short-term (≤14 days) ciprofloxacin use cannot be avoided, reduce cobimetinib dosage from 60 mg once daily to 20 mg once daily, then resume 60-mg daily dosage when ciprofloxacin is discontinued; select alternative anti-infective with no or mild CYP3A inhibitory activity if cobimetinib dosage is already reduced (40 or 20 mg once daily)
Cobicistat	Possible increased cobimetinib exposure	Avoid concomitant use
Dextromethorphan	No change in systemic exposure of single-dose dextromethorphan
Grapefruit or grapefruit juice	Possible increased cobimetinib exposure	Avoid concomitant use
Imatinib	Possible increased cobimetinib exposure	Avoid concomitant use
Macrolides (clarithromycin, erythromycin, telithromycin)	Clarithromycin, erythromycin, telithromycin: Possible increased cobimetinib exposure	Clarithromycin, erythromycin, telithromycin: Avoid concomitant use If short-term (≤14 days) erythromycin use cannot be avoided, reduce cobimetinib dosage from 60 mg once daily to 20 mg once daily, then resume 60-mg daily dosage when erythromycin is discontinued; select alternative anti-infective with no or mild CYP3A inhibitory activity if cobimetinib dosage is already reduced (40 or 20 mg once daily)
Midazolam	No change in systemic exposure of single-dose midazolam
Nefazodone	Possible increased cobimetinib exposure	Avoid concomitant use
Rabeprazole	No substantial effect on cobimetinib exposure
St. John’s wort (Hypericum perforatum)	Possible decreased systemic exposure and reduced efficacy of cobimetinib	Avoid concomitant use
Vemurafenib	No substantial effect on pharmacokinetics of either drug

Cobimetinib Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability is 46%.

Following oral administration, peak plasma concentrations are attained in 2.4 hours.

Mean systemic accumulation ratio is 2.4-fold when administered daily.

Steady-state concentrations are achieved in approximately 9 days.

Food

High-fat meal does not affect exposure.

Special Populations

In patients with mild or moderate hepatic impairment, systemic exposure similar to that in individuals with normal hepatic function; systemic exposure 31% lower in individuals with severe hepatic impairment.

In patients with mild or moderate renal impairment, systemic exposure similar to that in patients with normal renal function. Pharmacokinetics not studied in patients with severe renal impairment.

Age (19–88 years), gender, and ethnicity do not substantially affect pharmacokinetics.

Distribution

Extent

Not known whether cobimetinib is distributed into milk. (See Lactation under Cautions.)

Plasma Protein Binding

95%.

Elimination

Metabolism

Metabolized mainly by CYP3A and UGT2B7.

Elimination Route

Eliminated mainly in feces (76%) and to a lesser extent in urine (17.8%), mainly as metabolites.

Half-life

44 hours.

Stability

Storage

Oral

Tablets

Room temperature <30°C.

Actions

Potent, selective, reversible inhibitor of MEK 1 and 2 activation.
MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation.
Approximately 40–60% of cutaneous melanomas carry a BRAF mutation. Most common BRAF mutation is the substitution of glutamic acid for valine at codon 600 in exon 15 (BRAF V600E); mutation involving substitution of lysine for valine at codon 600 in exon 15 (BRAF V600K) occurs less frequently.
BRAF V600 mutations result in activation of BRAF pathway that includes MEK 1 and 2.
Mutation of BRAF V600E activates the mitogen-activated protein kinase (MAPK) and ERK signal transduction pathway, which enhances cell proliferation and tumor progression (e.g., metastasis).
Combination therapy with a BRAF inhibitor (i.e., dabrafenib, encorafenib, vemurafenib) and an MEK inhibitor (i.e., binimetinib, cobimetinib, trametinib) results in complete inhibition of the MAPK/ERK pathway.
Combination therapy with cobimetinib and vemurafenib resulted in increased apoptosis and reduced tumor growth of melanoma cell lines testing positive for BRAF V600E compared with either drug alone.
Prevents vemurafenib-mediated growth enhancement of wild-type BRAF tumor cell line in mice bearing tumor xenografts.

Advice to Patients

If a dose is missed or vomited, importance of taking the next dose at the regularly scheduled time; do not take an additional dose to replace the missed or vomited dose.
Risk of new primary cutaneous malignancies. Importance of contacting a clinician promptly if dermatologic changes (e.g., new wart, skin sore or reddish bump that bleeds or does not heal, mole that changes in size or color) occur.
Risk of hemorrhage. Importance of contacting a clinician promptly and seeking immediate medical attention if signs and/or symptoms of unusual bleeding (e.g., blood in stool or urine, unusual vaginal bleeding) occur.
Risk of cardiomyopathy. Importance of cardiac monitoring before and during cobimetinib therapy. Importance of contacting a clinician promptly if manifestations of left ventricular dysfunction (e.g., shortness of breath, persistent coughing or wheezing, fatigue, peripheral edema, tachycardia) occur.
Risk of serious adverse dermatologic effects. Importance of contacting a clinician promptly if a serious reaction (e.g., rash affecting a large area, blistering or peeling of skin) occurs.
Risk of serous retinopathy or retinal vein occlusion. Importance of contacting a clinician promptly if visual disturbances (i.e., blurred, distorted, partial, or halo vision) occur.
Risk of hepatotoxicity. Importance of liver function test monitoring before and during cobimetinib therapy. Importance of immediately reporting any possible manifestations of hepatotoxicity (e.g., jaundice, dark or tea-colored urine, nausea, vomiting, fatigue, loss of appetite).
Risk of rhabdomyolysis. Importance of monitoring CK concentrations before and during cobimetinib therapy. Importance of immediately reporting any possible manifestations of rhabdomyolysis (e.g., dark or red urine; muscle pain, spasms, or weakness).
Risk of photosensitivity reactions. Importance of using a broad-spectrum sunscreen and lip balm (SPF ≥30), wearing protective clothing, and avoiding exposure to sunlight during therapy. Importance of contacting a clinician if skin becomes red, painful, itchy, or warm; irritated; or thick, dry, or wrinkled; if bumps or small papules develop; or if a rash from sunlight exposure occurs.
Risk of fetal harm. Necessity of advising women of childbearing potential that they should use an effective method of contraception while receiving the drug and for ≥2 weeks after discontinuance of therapy. Importance of women informing clinicians if they are or plan to become pregnant. If pregnancy occurs, advise pregnant women of potential risk to the fetus.
Importance of advising women to avoid breast-feeding during and for 2 weeks after discontinuance of therapy.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses.
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.