PEMEtrexed

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Alimta: 500 mg (1 ea)

Solution Reconstituted, Intravenous [preservative free]:

Alimta: 100 mg (1 ea)

Pharmacology

Mechanism of Action

Pemetrexed is an antifolate; it disrupts folate-dependent metabolic processes essential for cell replication. Pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT), and aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), the enzymes involved in folate metabolism and DNA synthesis, resulting in inhibition of purine and thymidine nucleotide and protein synthesis.

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: 16.1 L

Metabolism

Minimal

Excretion

Urine (70% to 90% as unchanged drug)

Half-Life Elimination

Normal renal function: 3.5 hours

Protein Binding

81%

Use in Specific Populations

Special Populations: Renal Function Impairment

Pemetrexed clearance decreases and AUC increases as renal function decreases; in patients with CrCl of 45, 50, and 80 mL/minute, AUC was increased 65%, 54%, and 13%, respectively, compared with patients with CrCl of 100 mL/minute.

Use: Labeled Indications

Mesothelioma: Initial treatment of malignant pleural mesothelioma (in combination with cisplatin) that is unresectable or in patients who are not otherwise candidates for curative surgery

Non-small cell lung cancer (NSCLC), nonsquamous:

Initial treatment of locally advanced or metastatic nonsquamous NSCLC (in combination with cisplatin)

Initial treatment of metastatic, nonsquamous NSCLC (in combination with platinum chemotherapy and pembrolizumab) in patients with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations

Maintenance treatment (single-agent) of locally advanced or metastatic nonsquamous NSCLC if no progression after 4 cycles of platinum-based first-line therapy

Single-agent treatment (after prior chemotherapy) of recurrent/metastatic nonsquamous NSCLC

Limitation of use: Not indicated for the treatment of squamous cell NSCLC

Use: Off Label

Bladder cancer, metastaticb

Data from a phase II study support the use of pemetrexed as second-line treatment of locally advanced, metastatic, or relapsed transitional cell urothelium cancer Sweeny 2006.

Cervical cancer, persistent or recurrentb

Data from two phase II studies support the use of pemetrexed for persistent or recurrent cervical cancer Lorusso 2010, Miller 2008.

Malignant pleural mesothelioma (single agent and off-label combination)b

Data from two phase II studies support the use of pemetrexed in combination with carboplatin in the treatment of malignant pleural mesothelioma Castagneto 2008, Ceresoli 2006. Data from an expanded access study supports the use of pemetrexed as a single agent in the management of unresectable malignant pleural mesothelioma Taylor 2008.

Ovarian cancer, platinum-resistantb

Data from a phase II study support the use of pemetrexed in platinum-resistant epithelial ovarian or primary peritoneal cancer Vergote 2009.

Thymic malignancies, metastaticb

Data from a phase II study support the use of pemetrexed in previously treated unresectable advanced thymoma or thymic carcinoma Loehrer 2006.

Contraindications

Severe hypersensitivity to pemetrexed or any component of the formulation

Canadian labeling: Additional contraindications (not in the US labeling): Concomitant yellow fever vaccine

Dosage and Administration

Dosing: Adult

Note: Start vitamin supplements 1 week before initial pemetrexed dose: Folic acid 400 to 1,000 mcg orally once daily (begin 7 days prior to treatment initiation; continue daily during treatment and for 21 days after last pemetrexed dose) and vitamin B₁₂ 1,000 mcg IM 7 days prior to treatment initiation and then every 3 cycles. Give dexamethasone 4 mg orally twice daily for 3 days, beginning the day before treatment to minimize cutaneous reactions. New treatment cycles should not begin unless ANC ≥1,500/mm³, platelets ≥100,000/mm³, CrCl ≥45 mL/minute, and recovery of nonhematologic toxicity to ≤ grade 2.

Malignant pleural mesothelioma: IV: 500 mg/m² on day 1 of each 21-day cycle (in combination with cisplatin); continue until disease progression or unacceptable toxicity or (off-label) in combination with carboplatin (Castagneto 2008; Ceresoli 2006) or (off-label) as single-agent therapy (Taylor 2008)

Non-small cell lung cancer, nonsquamous: IV:

Initial treatment of locally advanced or metastatic NSCLC: 500 mg/m² on day 1 of each 21-day cycle (in combination with cisplatin) for up to 6 cycles or until disease progression or unacceptable toxicity

Initial treatment of metastatic NSCLC: 500 mg/m² on day 1 of each 21-day cycle (in combination with pembrolizumab and either carboplatin or cisplatin) for 4 cycles; following platinum-based therapy, may continue pemetrexed (alone or with pembrolizumab) as maintenance therapy until disease progression or unacceptable toxicity (Gandhi 2018)

Maintenance treatment of locally advanced or metastatic NSCLC (after 4 cycles of initial platinum-based therapy): 500 mg/m² on day 1 of each 21-day cycle (as a single-agent); continue until disease progression or unacceptable toxicity

Second-line treatment of recurrent/metastatic disease (after prior chemotherapy): 500 mg/m² on day 1 of each 21-day cycle (as a single-agent); continue until disease progression or unacceptable toxicity

Bladder cancer, metastatic (off-label use): IV: 500 mg/m² on day 1 of each 21-day cycle until disease progression or unacceptable toxicity (Sweeney 2006)

Cervical cancer, persistent or recurrent (off-label use): IV: 500 mg/m² on day 1 of each 21-day cycle until disease progression or unacceptable toxicity occurs (Lorusso 2010) or 900 mg/m² on day 1 of each 21-day cycle (Miller 2008)

Ovarian cancer, platinum-resistant (off-label use): IV: 500 mg/m² on day 1 of each 21-day cycle (Vergote 2009)

Thymic malignancies, metastatic (off-label use): IV: 500 mg/m² on day 1 of each 21-day cycle for 6 cycles or until disease progression or unacceptable toxicity occurs (Loehrer 2006)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Note: When used in combination with other agents (eg cisplatin, carboplatin, pembrolizumab), those agents may also require dosage modification.

Hematologic toxicity: Upon recovery, reinitiate therapy as follows:

ANC <500/mm³ and platelets ≥50,000/mm³: Reduce pemetrexed dose to 75% of previous dose

Platelets <50,000/mm³without bleeding: Reduce pemetrexed dose to 75% of previous dose

Platelets <50,000/mm³with bleeding: Reduce pemetrexed dose to 50% of previous dose

Recurrent grade 3 or 4 myelosuppression after 2 dose reductions: Discontinue

Nonhematologic toxicity: Withhold treatment until recovery to ≤ grade 2; upon recovery, reinitiate or discontinue therapy as follows:

Grade 3 or 4 toxicity (excluding mucositis and neurotoxicity): Reduce pemetrexed dose to 75% of previous dose

Grade 3 or 4 diarrhea or any diarrhea requiring hospitalization: Reduce pemetrexed dose to 75% of previous dose

Grade 3 or 4 mucositis: Reduce pemetrexed dose to 50% of previous dose

Grade 3 or 4 neurotoxicity: Permanently discontinue

Interstitial pneumonitis: Permanently discontinue

Radiation recall signs/symptoms: Permanently discontinue

Severe or life-threatening dermatologic toxicity: Permanently discontinue

Recurrent grade 3 or 4 nonhematologic toxicity after 2 dose reductions: Permanently discontinue

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient's actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

Reconstitution

Reconstitute with NS (preservative free); add 4.2 mL to the 100 mg vial and 20 mL to the 500 mg vial, resulting in a 25 mg/mL concentration. Gently swirl until powder is completely dissolved. Solution may be colorless to green-yellow. Further dilute in 100 mL NS prior to infusion (the manufacturer recommends a total volume of 100 mL).

Administration

IV: Infuse over 10 minutes. When used in combination with platinum-based therapy (cisplatin or carboplatin), administer pemetrexed prior to the platinum. Administer pemetrexed after pembrolizumab if administered on the same day.

Dietary Considerations

Initiate folic acid supplementation 1 week before first dose of pemetrexed, continue for full course of therapy, and for 21 days after last pemetrexed dose. Institute vitamin B₁₂ 1 week before the first dose; administer every 9 weeks thereafter.

Storage

Store intact vials at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Reconstituted solution and solution diluted for infusion are stable for 24 hours when refrigerated at 2°C to 8°C (36°F to 46°F).

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Ibuprofen: May increase the serum concentration of PEMEtrexed. Management: In patients with an estimated creatinine clearance of 45 to 79 mL/min, avoid ibuprofen for 2 days before, the day of, and 2 days following the administration of pemetrexed. Monitor for increased pemetrexed toxicities if combined. Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nitisinone: May increase the serum concentration of OAT1/3 Substrates. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Pretomanid: May increase the serum concentration of OAT1/3 Substrates. Monitor therapy

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Pyrimethamine: May enhance the adverse/toxic effect of PEMEtrexed. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Teriflunomide: May increase the serum concentration of OAT1/3 Substrates. Monitor therapy

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Tolvaptan: May increase the serum concentration of OAT1/3 Substrates. Management: Patients being treated with the Jynarque brand of tolvaptan should avoid concomitant use of OAT1/3 substrates. Concentrations and effects of the OAT1/3 substrate would be expected to increase with any combined use. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

>10%:

Central nervous system: Fatigue (18% to 34%)

Dermatologic: Desquamation (≤14%), skin rash (≤14%)

Gastrointestinal: Nausea (12% to 31%), anorexia (19% to 22%), vomiting (6% to 16%), stomatitis (≤15%), diarrhea (5% to 13%)

Hematologic & oncologic: Anemia (15% to 19%; grades 3/4: 3% to 5%), neutropenia (6% to 11%; grades 3/4: 3% to 5%)

Respiratory: Pharyngitis (≤15%)

1% to 10%:

Cardiovascular: Edema (5%)

Central nervous system: Neuropathy (sensory: 9%; motor: ≤5%)

Dermatologic: Pruritus (7%), alopecia (6%), erythema multiforme (≤5%)

Gastrointestinal: Constipation (6%), abdominal pain (1% to <5%)

Hematologic & oncologic: Thrombocytopenia (8%; grades 3/4: 2%), febrile neutropenia (<5%)

Hepatic: Increased serum alanine aminotransferase (8% to 10%), increased serum aspartate aminotransferase (7% to 8%)

Hypersensitivity: Hypersensitivity reaction (<5%)

Infection: Infection (1% to <5%), sepsis (1%)

Ophthalmic: Conjunctivitis (≤5%), increased lacrimation (1% to <5%)

Miscellaneous: Fever (8%)

<1%, postmarketing, and/or case reports: Bullous rash, cardiac arrhythmia, colitis, depression, esophagitis, gastrointestinal obstruction, hemolytic anemia, interstitial pneumonitis, pain, pancreatitis, pulmonary embolism, radiation recall phenomenon, renal failure syndrome, Stevens-Johnson syndrome, supraventricular cardiac arrhythmia, syncope, toxic epidermal necrolysis, ventricular tachycardia

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Pemetrexed may cause severe myelosuppression, including anemia, neutropenia, thrombocytopenia and/or pancytopenia; frequent laboratory monitoring is necessary (myelosuppression is often dose-limiting). Severe myelosuppression may require blood transfusion. Prophylactic folic acid and vitamin B₁₂ supplements are necessary to reduce hematologic toxicity, febrile neutropenia and infection; initiate supplementation 1 week before the first dose of pemetrexed and continue for 21 days after the last pemetrexed dose (the risk for myelosuppression is higher in patients who did not receive vitamin supplementation). Monitor blood counts at the beginning of each cycle, and as clinically indicated. Dose reductions in subsequent cycles may be required due to myelosuppression.
• Cutaneous reactions: Serious and occasionally fatal dermatologic toxicity may occur; pretreatment with dexamethasone is necessary to reduce the incidence and severity of cutaneous reactions. Rarely, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Permanently discontinue pemetrexed for severe and life-threatening bullous, blistering, or exfoliating dermatologic toxicity.
• Gastrointestinal toxicity: Gastrointestinal toxicity may occur; prophylactic folic acid and vitamin B₁₂ supplements are necessary to reduce gastrointestinal toxicity. Initiate supplementation 1 week before the first dose of pemetrexed and continue for 21 days after the last pemetrexed dose.
• Hypersensitivity: Hypersensitivity (including allergic reaction) has been reported with pemetrexed.
• Nephrotoxicity: Pemetrexed may cause severe (and potentially fatal) renal toxicity (renal toxicity may occur with single-agent pemetrexed or when used in combination with other chemotherapy agents). Measure creatinine clearance prior to each dose and monitor renal function throughout treatment. May require therapy discontinuation. Withhold pemetrexed treatment for creatinine clearance <45 mL/minute.
• Pulmonary toxicity: Interstitial pneumonitis has been observed with use; may be serious and/or fatal. Interrupt therapy and evaluate promptly for acute onset new or progressive pulmonary symptoms (eg, dyspnea, cough, or fever). If interstitial pneumonitis is confirmed, permanently discontinue pemetrexed.
• Radiation recall: Radiation recall may occur in patients administered pemetrexed who received radiation previously (weeks to years). Monitor for inflammation or blistering in areas of prior radiation treatment; permanently discontinue pemetrexed if radiation recall is confirmed.

Disease-related concerns:

• Renal impairment: Pemetrexed is primarily cleared by the kidneys; decreased renal function results in increased toxicity. The manufacturer does not recommend use if CrCl <45 mL/minute. Use caution in patients receiving concurrent nephrotoxins; may result in delayed pemetrexed clearance.
• Third space fluid: Although the effect of third space fluid on pemetrexed pharmacokinetics has not been fully defined, studies have determined pemetrexed concentrations in patients with mild-to-moderate ascites/pleural effusions were similar to concentrations in trials of patients without third space fluid accumulation.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Ibuprofen: Ibuprofen may reduce the clearance of pemetrexed. In patients with CrCl 45 to 79 mL/minute, interrupt ibuprofen therapy 2 days prior to, during, and 2 days after pemetrexed therapy. If concomitant use cannot be avoided, monitor for myelosuppression, renal, and gastrointestinal toxicity.

Monitoring Parameters

CBC with differential and platelets (before each cycle, on days 8 and 15 of each cycle, and as needed; monitor for nadir and recovery); renal function tests (serum creatinine, creatinine clearance, BUN; prior to each cycle and as needed) total bilirubin, ALT, AST (periodic); signs/symptoms of mucositis and diarrhea, pulmonary toxicity, dermatologic toxicity, and radiation recall.

Pregnancy

Pregnancy Considerations

Based on findings in animal reproduction studies and on the mechanism of action, pemetrexed may cause fetal harm if administered to a pregnant female. Females of reproductive potential should use effective contraception during treatment and for at least 6 months after the last pemetrexed dose. Males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last pemetrexed dose. Pemetrexed may impair fertility in males.

Patient Education

What is this drug used for?

• It is used to treat lung cancer.
• It is used to treat mesothelioma.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Nausea
• Vomiting
• Diarrhea
• Constipation
• Mouth sores
• Change in taste
• Lack of appetite
• Hair loss

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Dehydration like dry skin, dry mouth, dry eyes, increased thirst, fast heartbeat, dizziness, fast breathing, or confusion
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting.
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit
• Kidney problems like not able to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes
• Severe pulmonary disorder like lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse.
• Swelling
• Severe loss of strength and energy
• Severe mouth pain or irritation
• Burning or numbness feeling
• Pale skin
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.