What is Rasuvo (methotrexate)?

What is Rasuvo (Methotrexate)?

Rasuvo is a single-use auto-injector formulation of subcutaneous methotrexate, FDA-approved for treating severe psoriasis, rheumatoid arthritis, and polyarticular juvenile idiopathic arthritis. 1, 2

Drug Formulation and Availability

• Rasuvo is a preservative-free methotrexate injection supplied as a subcutaneous auto-injector device 1, 2
• Outside the USA, equivalent formulations are marketed as Metoject® or Metex® 2
• Another similar subcutaneous auto-injector product available in the USA is Otrexup™ 2
• The formulation contains methotrexate sodium with sodium chloride as an inactive ingredient, with pH adjusted to 7.0-9.0 1

FDA-Approved Indications

Rasuvo (methotrexate injection) is indicated for:

• Treatment of adults with severe psoriasis 1
• Treatment of adults with rheumatoid arthritis (RA) 1
• Treatment of pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA) 1
• Various neoplastic diseases including acute lymphoblastic leukemia, non-Hodgkin lymphoma, osteosarcoma, breast cancer, head and neck cancer, and gestational trophoblastic neoplasia 1

Mechanism of Action

• Methotrexate is a folate analog metabolic inhibitor that inhibits dihydrofolic acid reductase 1
• This enzyme is required to convert dihydrofolates to tetrahydrofolates, which are essential carriers of one-carbon groups in purine nucleotide and thymidylate synthesis 1
• By interfering with DNA synthesis, repair, and cellular replication, methotrexate preferentially affects actively proliferating tissues including malignant cells, bone marrow, and mucosal cells 1
• The specific mechanism of action in rheumatoid arthritis, pJIA, and psoriasis remains unknown 1

Advantages of Subcutaneous Formulation

• Subcutaneous methotrexate reduces gastrointestinal side effects compared to oral formulation, which is a major reason for treatment discontinuation 3
• The subcutaneous route improves drug bioavailability and reduces variation, particularly at higher doses where oral absorption becomes unreliable 3
• Subcutaneous administration may allow patients to overcome oral intolerance and improve drug survival 3
• In European countries, subcutaneous methotrexate is recommended as first-line treatment, while in the USA it is established as second-line therapy 3

Clinical Efficacy

Psoriasis

• Methotrexate is the most commonly prescribed traditional systemic therapy worldwide for psoriasis 4
• FDA approval was granted in 1972 for severe, recalcitrant, disabling psoriasis 4
• In comparative studies, methotrexate achieved PASI 75 response in 60% of patients at 16 weeks 4
• Methotrexate can be dramatically effective even in the most severe cases of psoriasis 4

Rheumatoid Arthritis

• Methotrexate is the disease-modifying antirheumatic drug (DMARD) of first choice for RA treatment 4
• Low-dose weekly methotrexate (10-25 mg/week) demonstrates superior efficacy compared to placebo and comparable efficacy to anti-TNF therapy 5
• At 1 year, one-third of patients on methotrexate show no radiographic progression 5
• Methotrexate is now the cornerstone of RA therapy and the most popular drug worldwide for this indication 5

Dosing and Administration

Starting Doses

• Rheumatoid arthritis: Start with 10-15 mg/week orally or subcutaneously, with dose escalation of 5 mg every 2-4 weeks up to 20-30 mg/week based on clinical response and tolerability 6
• Psoriasis: 10-25 mg/week 6
• Inflammatory bowel disease: 25 mg/week intramuscularly for induction, 15 mg/week for maintenance 6

Renal Impairment Adjustments

• eGFR >90 mL/min: Normal dose 4, 6
• eGFR 20-50 mL/min: Half dose 4, 6
• eGFR <20 mL/min: Avoid methotrexate 4, 6
• Methotrexate is contraindicated in RA patients with eGFR <30 mL/minute 7

Monitoring Requirements

Initial Monitoring

• Complete blood count (CBC) with differential: Every 2-4 weeks for the first few months 4, 6
• Liver function tests (AST, ALT, albumin, bilirubin): Monthly initially 6
• Renal function (creatinine, eGFR): Every 2-3 months 6

Ongoing Monitoring

• CBC and platelet counts: Every 1-3 months depending on dose adjustments and previous results 4, 6
• Liver function tests: Every 2-3 months based on dose adjustments 4, 6
• Increase monitoring frequency to every 2-4 weeks after any dose adjustment 8

Pre-treatment Work-up

• History and physical examination 4
• CBC and platelet counts 4
• BUN, creatinine, and liver function tests 4
• Hepatitis B/C serology 4
• Pregnancy test in women of childbearing potential 4
• Consider PPD (tuberculosis screening) 4
• Consider chest radiograph if underlying pulmonary disease 4

Toxicity and Side Effects

Common Adverse Effects

• Gastrointestinal symptoms (nausea, vomiting, diarrhea, stomatitis) occur in up to 25% of patients 6
• Gastrointestinal toxicity is the most common reason for treatment discontinuation 5
• Mucositis and oral ulceration are frequent dose-related effects 1

Serious Toxicities

• Hepatotoxicity: May lead to fibrosis and cirrhosis with long-term use 6
• Pulmonary toxicity: Pneumonitis and fibrosis are rare but serious complications 6
• Bone marrow suppression: Leukopenia, thrombocytopenia, anemia, pancytopenia, and myelosuppression 1, 7
• Nephrotoxicity: Particularly with high-dose therapy 7
• Increased risk of infections due to immunosuppression 7

Hepatotoxicity Monitoring

• Liver biopsy is indicated only in patients with significant liver disease history 4
• For patients without risk factors, consider liver biopsy after cumulative doses exceeding 3.5-4 g 4
• For high-risk patients (diabetes, obesity, abnormal liver function tests, excessive alcohol use, chronic liver disease), consider baseline biopsy or at 6 months with subsequent biopsies after 1-1.5 g cumulative dose 4
• Rheumatology guidelines for methotrexate monitoring are less stringent than dermatology guidelines, likely because psoriasis patients are more prone to obesity and underlying nonalcoholic steatohepatitis 4

Risk Mitigation Strategies

Folic Acid Supplementation

• Administer at least 5 mg of folic acid per week to reduce gastrointestinal and liver toxicity without reducing efficacy 6
• Folic acid supplementation (1-5 mg daily except on the day of methotrexate) reduces hematologic toxicity 8
• Leucovorin is highly beneficial in preventing myelosuppression, gastric toxicity, and neurotoxic effects after high-dose methotrexate therapy 7

Drug Interactions to Avoid

• NSAIDs: Can reduce renal elimination of methotrexate, leading to toxicity; case reports document significant morbidity and mortality with naproxen, diclofenac, ibuprofen, and indomethacin 4
• Trimethoprim-sulfamethoxazole: Increases methotrexate toxicity risk 8
• Penicillins: May interact with methotrexate 8
• Proton pump inhibitors: Potential interaction 8
• Drugs that displace methotrexate from plasma albumin (sulfonamides, salicylates, tetracyclines, chloramphenicol, phenytoin) increase toxicity risk 1

Alcohol Limitation

• Limit alcohol consumption due to increased risk of hepatotoxicity 6
• Excessive alcohol ingestion is a risk factor requiring more intensive hepatotoxicity monitoring 4

Absolute Contraindications

• Pregnancy (Category X) 4, 6
• Breastfeeding 4, 6
• Significant hepatic damage or cirrhosis 4, 6
• Severe renal impairment (eGFR <20 mL/min) 6
• Bone marrow suppression (anemia, leukopenia, thrombocytopenia) 6

Pregnancy and Conception

• Women must wait at least 3 months after discontinuing methotrexate before attempting to conceive 4, 6
• Men must wait 3 months after discontinuation before attempting to father children 6
• Methotrexate is a teratogen, abortifacient, and decreases sperm count 4

Overdosage Management

Manifestations

• Hematologic reactions: leukopenia, thrombocytopenia, anemia, pancytopenia, myelosuppression 1
• Gastrointestinal reactions: mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration or bleeding 1
• Severe complications: sepsis, septic shock, renal failure, aplastic anemia 1
• CNS symptoms with intrathecal overdosage: headache, nausea, vomiting, seizures, acute toxic encephalopathy 1

Treatment

• Administer leucovorin or levoleucovorin as soon as possible after overdosage 1
• Monitor serum methotrexate concentrations closely to guide leucovorin/levoleucovorin therapy 1
• Glucarpidase is indicated for toxic methotrexate concentrations (>1 μmol/L) in patients with delayed clearance due to impaired renal function 1, 7
• Do not administer leucovorin within 2 hours before or after glucarpidase, as leucovorin is a substrate for glucarpidase 1
• Hydration and urinary alkalinization may prevent precipitation of methotrexate in renal tubules 1
• Acute intermittent hemodialysis using a high-flux dialyzer can effectively clear methotrexate 1

Pharmacokinetics

• Initial volume of distribution: approximately 0.18 L/kg (18% of body weight) 1
• Steady-state volume of distribution: 0.4-0.8 L/kg (40-80% of body weight) 1
• Approximately 50% protein bound in serum 1
• Terminal half-life: 3-10 hours for low-dose therapy (psoriasis, RA); 8-15 hours for high-dose therapy 1
• Does not penetrate blood-cerebrospinal fluid barrier in therapeutic amounts when given parenterally 1
• Primarily eliminated via kidneys with renal tubular excretion and reabsorption 1, 7

Combination Therapy

• Methotrexate has been used in combination with all approved biologic agents for psoriasis, with greatest experience using TNF inhibitors 4
• Methotrexate suppresses antibodies against monoclonal TNF inhibitors (adalimumab and infliximab) 4
• Whether methotrexate combined with biologics causes additive immunosuppression remains uncertain 4
• Methotrexate is useful for treating both skin and joint manifestations in psoriatic arthritis, unlike NSAIDs which occasionally worsen skin disease 4