Methotrexate Prescribing Information
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- Methotrexate Injection can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, Methotrexate Injection is contraindicated in pregnancy. Advise females and males of reproductive potential to use effective contraception [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)].
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- Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis [see Contraindications (4) and Warnings and Precautions (5.2)].
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- Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis. Use only preservative-free Methotrexate Injection for treatment of neonates or low-birth weight infants and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available [see Dosage and Administration (2.1) and Warnings and Precautions (5.3)].
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- Other serious adverse reactions, including death, have been reported with methotrexate. Closely monitor for infections and adverse reactions of the bone marrow, kidneys, liver, nervous system, gastrointestinal tract, lungs, and skin. Withhold or discontinue Methotrexate Injection as appropriate [see Warnings and Precautions (5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 5.10, 5.11)].
Acute Lymphoblastic Leukemia
Methotrexate Injection is indicated for the treatment of adult and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy regimen.
Meningeal Leukemia: Prophylaxis and Treatment
Methotrexate Injection is indicated for the prophylaxis and treatment of meningeal leukemia in adult and pediatric patients.
Non-Hodgkin Lymphoma
Methotrexate Injection is indicated for the treatment of adults and pediatric patients with Non-Hodgkin lymphoma.
Osteosarcoma
Methotrexate Injection is indicated for the treatment of adults and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen.
Breast Cancer
Methotrexate Injection is indicated for the treatment of adults with breast cancer as part of a combination chemotherapy regimen.
Squamous Cell Carcinoma of the Head and Neck
Methotrexate Injection is indicated for the treatment of adults with squamous cell carcinoma of the head and neck as a single-agent.
Gestational Trophoblastic Neoplasia
Methotrexate Injection is indicated for the treatment of adults with gestational trophoblastic neoplasia (GTN) as part of a combination chemotherapy regimen.
Rheumatoid Arthritis
Methotrexate Injection is indicated for the treatment of adults with rheumatoid arthritis (RA).
Polyarticular Juvenile Idiopathic Arthritis
Methotrexate Injection is indicated for the treatment of pediatric patients with polyarticular Juvenile Idiopathic Arthritis (pJIA).
Psoriasis
Methotrexate Injection is indicated for the treatment of adults with severe psoriasis.
Important Dosage and Safety Information
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- Use only preservative-free Methotrexate Injection for treatment of neonates or low-birth weight infants and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4)].
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- Verify pregnancy status in females of reproductive potential before starting Methotrexate Injection [see Contraindications (4) and Warnings and Precautions (5.1)].
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- For patients switching between a methotrexate product administered orally and Methotrexate Injection, consider potential differences in bioavailability.
Recommended Monitoring and Concomitant Therapies for Intermediate- and High-Dose Regimens
To decrease the risk of severe adverse reactions [see Warnings and Precautions (5)]:
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- Administer leucovorin rescue in patients receiving Methotrexate Injection doses of 500 mg/m2 or greater (e.g., high-dose).
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- Consider leucovorin rescue for patients receiving Methotrexate Injection doses between 100 mg/m2 to less than 500 mg/m2 (e.g., intermediate-dose).
Refer to the leucovorin Prescribing Information for additional information.
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- For high-dose Methotrexate Injection regimens, follow the supportive care and monitoring instructions below. Also consider for patients receiving intermediate-dose Methotrexate Injection regimens.
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- Monitor serum creatinine, electrolytes, at baseline and at least daily during therapy
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- Administer intravenous fluids starting before the first dose and continuing throughout treatment to maintain adequate hydration and urine output
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- Alkalinize urine starting before the first dose and continuing throughout treatment to maintain a urinary pH of 7 or higher
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- Monitor methotrexate concentrations at least daily and adjust hydration and leucovorin dosing as needed
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- Administer glucarpidase in patients who have toxic plasma methotrexate concentrations (>1 micromole per liter) and delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase Prescribing Information for additional information)
Recommended Dosage for Acute Lymphoblastic Leukemia
Methotrexate Injection is used as part of a multi-drug regimen. The recommended dosage varies from 10 to 5000 mg/m2 intravenously. For high dose Methotrexate Injection regimens, use leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration (2.2)]. Lower doses (e.g., 20 to 30 mg/m2/week) may be used intramuscularly. Individualize the dose and schedule of Methotrexate Injection based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment.
Recommended Dosage for Meningeal Leukemia: Prophylaxis and Treatment
Use only preservative-free Methotrexate Injection for intrathecal use.
Prior to administration, dilute preservative-free Methotrexate Injection to a concentration of 1 mg/mL in preservative-free 0.9% Sodium Chloride Injection, USP.
The recommended intrathecal dose of Methotrexate Injection (preservative-free) is based on age:
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- less than 1 year: 6 mg
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- 1 to less than 2 years: 8 mg
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- 2 to less than 3 years: 10 mg
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- 3 to less than 9 years: 12 mg
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- greater than or equal to 9 years: 12 to15 mg
For treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 or more days up to twice weekly; however, administration at intervals of less than 1 week may result in increased subacute toxicity. For meningeal leukemia prophylaxis, Methotrexate Injection is administered no more than once weekly.
For patients with Down Syndrome, administer leucovorin rescue with intrathecal Methotrexate Injection.
Recommended Dosage for Non-Hodgkin Lymphoma
The recommended dosage of Methotrexate Injection varies. When used in combination, recommended dosages range from 10 mg/m2 to 8000 mg/m2 intravenously. When used as a single agent, recommended dosages include 8,000 mg/m2 intravenously for central nervous system-directed therapy or 5 to 75 mg intravenously for cutaneous forms of Non-Hodgkin lymphoma.
As part of a combination chemotherapy regimen, a recommended dosage of Methotrexate Injection is 1,000 mg/m2 or 3,000 mg/m2 as an intravenous infusion over 24 hours followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration (2.2)].
For central nervous system-directed therapy, a recommended dosage of Methotrexate Injection is 8,000 mg/m2 as an intravenous infusion over 4 hours as a single agent or in combination with immunochemotherapy at doses ranging from 3,000 mg/m2 to 8,000 mg/m2 followed by leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration (2.2)].
For intrathecal Methotrexate Injection (preservative-free), the recommended dose is based on age [see Dosage and Administration (2.4)]. The frequency of administration varies based on whether it is being used for treatment or prophylaxis, and other factors.
Recommended Dosage for Osteosarcoma
The recommended dosage of Methotrexate Injection is typically 12 g/m2 (maximum 20 g/dose) as an intravenous infusion over 4 hours administered as a component of a combination chemotherapy regimen. Administer leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration (2.2)]. Subsequent doses may need to be adjusted based on observed peak serum methotrexate concentrations. Dosage and schedule may vary based upon factors such as patient comorbidities, disease state, and prior treatments.
Recommended Dosage for Breast Cancer
A recommended dosage of Methotrexate Injection is 40 mg/m2 intravenously as a component of a cyclophosphamide- and fluorouracil-based multi-drug regimen.
Recommended Dosage for Squamous Cell Carcinoma of Head and Neck
The recommended dosage of Methotrexate Injection ranges from 40 to 60 mg/m2 intravenously once weekly.
Recommended Dosage for Gestational Trophoblastic Neoplasia
For patients with low-risk gestational trophoblastic neoplasia (GTN) a recommended dosage for Methotrexate Injection is 30 mg/m2 to 200 mg/m2 or 0.4 mg/kg to1 mg/kg intravenously or intramuscularly.
For patients with high-risk GTN, a recommended dosage for Methotrexate Injection is 300 mg/m2 over 12 hours as an intravenous infusion as a component of a multi-drug regimen.
Recommended Dosage for Rheumatoid Arthritis
The recommended starting dosage of Methotrexate Injection is 7.5 mg once weekly, administered intramuscularly with escalation to achieve optimal response. Dosages of more than 20 mg once weekly result in an increased risk of serious adverse reactions, including myelosuppression.
When responses are observed, the majority occurred between 3 and 6 weeks from initiation of treatment; however, responses have occurred up to 12 weeks after treatment initiation.
Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.12)].
Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis
The recommended starting dosage of Methotrexate Injection is 10 mg/m2 once weekly administered subcutaneously or intramuscularly, with escalation to achieve optimal response. Dosages over 30 mg/ m2 per week may result in an increased risk of serious adverse reactions, including myelosuppression. When responses are observed, the majority occurred between 3 and 6 weeks from initiation of treatment; however, responses have occurred up to 12 weeks after treatment initiation.
Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.12)].
Recommended Dosage for Psoriasis
The recommended dosage of Methotrexate Injection is 10 mg to 25 mg intramuscularly or intravenously once weekly until adequate response is achieved.
Adjust the dose gradually to achieve optimal clinical response; do not exceed 25 mg per week. Once optimal clinical response has been achieved, reduce the dosage to the lowest possible dosing regimen.
Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.12)].
Dosage Modifications for Adverse Reactions
Discontinue Methotrexate Injection for:
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- Anaphylaxis or other severe hypersensitivity reactions [see Warnings and Precautions (5.2)]
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- Lymphoproliferative disease [see Warnings and Precautions (5.13)]
Withhold, dose reduce or discontinue Methotrexate Injection as appropriate for:
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- Myelosuppression [see Warnings and Precautions (5.4)]
Withhold or discontinue Methotrexate Injection as appropriate for:
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- Serious infections [see Warnings and Precautions (5.5)]
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- Renal toxicity [see Warnings and Precautions (5.6)]
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- Hepatotoxicity [see Warnings and Precautions (5.7)]
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- Neurotoxicity [see Warnings and Precautions (5.8)]
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- Gastrointestinal toxicity [see Warnings and Precautions (5.9)]
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- Pulmonary toxicity [see Warnings and Precautions (5.10)]
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- Dermatologic reactions [see Warnings and Precautions (5.11)]
Administration and Handling Information
Methotrexate Injection is a hazardous drug. Follow applicable special handling and disposable procedures.1
With Preservative (multiple-dose vial)
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- Methotrexate Injection formulation containing benzyl alcohol as a preservative may be administered by intramuscular, intravenous, or subcutaneous injection [see Dosage and Administration (2.1)]. Methotrexate Injection with preservative may be further diluted with 0.9% Sodium Chloride Injection, USP. Diluted product should be used within 4 hours when stored at room temperature (20°C to 25°C) or 24 hours under refrigeration (2°C to 8°C).
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- Visually inspect product for particulate matter and discoloration prior to administration. Discard if particulate matter or discoloration is observed.
Preservative-free (single-dose vial)
Methotrexate Injection preservative-free may be administered by intramuscular, intravenous, subcutaneous, or intrathecal injection.
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- Use only preservative-free Methotrexate Injection for treatment of neonates or low-birth weight infants and for intrathecal use [see Warning and Precautions (5.3) and Use in Specific Populations (8.4)].
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- Use preservative-free Methotrexate Injection for high-dose regimens unless immediate treatment is required, and preservative-free formulations are not available [see Warning and Precautions (5.3) and Use in Specific Populations (8.4)].
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- Preservative-free Methotrexate Injection may be further diluted before use with preservative-free 0.9% Sodium Chloride Injection, USP. Diluted product should be used within 4 hours when stored at room temperature (20°C to 25°C) or 24 hours when stored under refrigeration (2°C to 8°C).
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- Visually inspect for particulate matter and discoloration prior to administration. Discard if particulate matter or discoloration is observed.
Injection: Methotrexate Injection is a clear, yellow solution and is supplied in single-dose vials (preservative-free) and multiple-dose vials (with preservative) in the following strengths:
With preservative (multiple-dose vial)
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- 50 mg/2 mL (25 mg/mL)
Preservative-free (single-dose vial)
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- 1 g/40 mL (25 mg/mL)
Pregnancy
Risk Summary
Methotrexate Injection is contraindicated in pregnant women with non-neoplastic diseases. Based on published reports and its mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology (12.1)]. There are no animal data that meet current standards for nonclinical developmental toxicity studies. Advise pregnant women with neoplastic diseases of the potential risk to a fetus. The preservative benzyl alcohol can cross the placenta; when possible, use the preservative-free formulation when Methotrexate Injection is needed during pregnancy to treat a neoplastic disease [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4)].
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Data
Human Data
Published data from case reports, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, CNS abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure.
A prospective multicenter study evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg/week after conception. The rate of spontaneous abortion/miscarriage in pregnant women exposed to methotrexate was 42.5% (95% confidence interval [95% CI] 29.2–58.7), which was higher than in unexposed patients with autoimmune disease (22.5%, 95% CI 16.8–29.7) and unexposed patients with non-autoimmune disease (17.3%, 95% CI 13–22.8). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in unexposed patients with autoimmune disease (adjusted odds ratio (OR) 1.8 [95% CI 0.6–5.7]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI 1.03–9.5]) (2.9%). Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.
Lactation
Risk Summary
Limited published literature reports the presence of methotrexate in human milk in low amounts, with the highest breast milk to plasma concentration ration reported to be 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions from methotrexate in breastfed infants, advise women not to breastfeed during treatment with Methotrexate Injection and for 1 week after the final dose.
Females and Males of Reproductive Potential
Methotrexate can cause malformations and fetal death at doses less than or equal to the recommended clinical doses [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating Methotrexate Injection [see Contraindications (4) and Use in Specific Populations (8.1)].
Contraception
Females
Advise females of reproductive potential to use effective contraception during and for 6 months after the final dose of Methotrexate Injection therapy.
Males
Methotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during and for 3 months after the final dose of Methotrexate Injection therapy.
Infertility
Females
Based on published reports of female infertility after therapy with methotrexate, advise females of reproductive potential that Methotrexate Injection can cause impairment of fertility and menstrual dysfunction during and after cessation of therapy. It is not known if the infertility may be reversed in all affected females.
Males
Based on published reports of male infertility after therapy with methotrexate, advise males that Methotrexate Injection can cause oligospermia or infertility during and after cessation of therapy. It is not known if the infertility may be reversed in all affected males.
Pediatric Use
The safety and effectiveness of Methotrexate Injection in pediatric patients have been established for ALL, meningeal leukemia prophylaxis and treatment, non-Hodgkin lymphoma, osteosarcoma and in pJIA. Clinical studies evaluating the use of methotrexate in pediatric patients with pJIA demonstrated safety comparable to that observed in adults with RA [see Adverse Reactions (6.1)]. The safety and effectiveness of Methotrexate Injection have not been established in pediatric patients for the treatment of breast cancer, squamous cell carcinoma of the head and neck, gestational trophoblastic neoplasia, rheumatoid arthritis, and psoriasis. Additional risk information is described below.
Risks of Serious Adverse Reactions due to Benzyl Alcohol-Preservative
Due to the risk of serious adverse reactions and fatal gasping syndrome following administration of intravenous solutions containing the preservative benzyl alcohol in neonates, use only preservative-free Methotrexate Injection in neonates and low-birth weight infants. The "gasping syndrome" is characterized by CNS depression, metabolic acidosis, and gasping respirations.
Serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature neonates and low-birth weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions include gradual neurological deterioration, seizures, intracranial hemorrhage, hematological abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.
When prescribing in infants (non-neonate, non-low-birth weight), if a preservative-free formulation of Methotrexate Injection is not available and use of a benzyl alcohol-containing formulation is necessary, consider the combined daily metabolic load of benzyl alcohol from all sources including Methotrexate Injection (Methotrexate Injection contains 9.4 mg of benzyl alcohol/per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known.
Do not administer methotrexate formulations containing benzyl alcohol intrathecally due to the risk of severe neurotoxicity [see Warnings and Precautions (5.3)].
Leukemia/Lymphoma
Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 g/m2) [see Warnings and Precautions (5.8)].
Geriatric Use
Clinical studies of methotrexate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Renal Impairment
Methotrexate elimination is reduced in patients with renal impairment [creatinine clearance (CLcr) less than 90 mL/min, calculated using Cockcroft-Gault] [see Clinical Pharmacology (12.3)]. Patients with renal impairment are at increased risk for methotrexate adverse reactions.
Follow recommendations to promote methotrexate elimination and decrease risk of acute kidney injury and other methotrexate toxicities in patients who are receiving intermediate- or high-dose regimens [see Dosage and Administration (2.2) and Warnings and Precautions (5.6)]. Consider reducing the dose or discontinuing Methotrexate Injection in patients with renal impairment as appropriate.
Hepatic Impairment
The pharmacokinetics and safety of methotrexate in patients with hepatic impairment is unknown Patients with hepatic impairment may be at increased risk for methotrexate adverse reaction based on elimination characteristics of methotrexate [see Clinical Pharmacology (12.3)]. Consider reducing the dose or discontinuing Methotrexate Injection in patients with hepatic impairment as appropriate [see Warnings and Precautions (5.7)].
Methotrexate Injection is contraindicated in:
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- Patients with history of severe hypersensitivity to methotrexate [see Warnings and Precautions (5.2)].
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- Pregnancy in patients with non-neoplastic diseases [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].