Dose:
0.67 g/kg for 3 days (ie Total Dose is 2g/kg).
0.4g/kg for 5 days for patients with history of thrombosis
0.4g/kg for 5 days for patients > 60y/o
0.4g/kg for 5 days for Serum Creatinine > 150umol/l
Give 1st 5g bottle over 1 hour.
Then subsequent bottles at 1/2 hour each.
Side Effects:
IVIG is potentially nephrotoxic!
(ARF can occur in pt with pre-existing renal impairment. Renal recovery is usually complete within 10 days)
(But I have seen 1 doctor's dad who went into ESRD following IVIG infusions. Please be careful)
Common side effects: fever, chills, backache, malaise.
Headache/Backache and chills usu respond to slowing of the infusion rate
Rarely, allergic reactions occur.
Patients with autoimmune disease often experience 'flu-like' symptoms and headaches for 7-10days after IVIG infusion.
Rarely, they may experience rashes and other inflammatory phenomena.
Haemodialysis patients:
Dose: 0.67g/kg given after 3 consecutive dialysis sessions (Total dose 2g/kg)
IVIG can be administered through the venous return limb of the extracorporeal circuit.
IVIG may be started during the HD session or given entirely at the end of the HD session via the venous limb of the fistula.
Following completion of the infusion, it is safe for the patient ot go home 1 hour after initial treatment.
CAPD patients:
As in normal patients but beware of fluid overload.
Showing posts with label Vasculitis. Show all posts
Showing posts with label Vasculitis. Show all posts
Thursday, December 11, 2008
Thursday, December 4, 2008
Campath (Alemtuzumab)
DNA derived humanized monoclonal antibodyy.
Targeted against CD52.
CD52 is epressed on surface of normal and malignant B and T lymphocytes, NK cells, monocytes, macrophages, tissues of the male reproductive system.
Erythrocytes or hematopoetic stem cells do not have CD52.
Mature sperms have CD52.
Skin and male reproductive tract hace CD52.
Mechanism of action: antibody dependent lysis of leukemic cells following cell surface binding.
Lab monitoring: FBC weekly. CD4 counts.
About 2% risk of antibodies towards Campth (may cross react with other monoclonals)
No long term studies on Carcinogenesis, Mutagenesis, Impairment of fertility
Contraception should be used in childbearing women and men during Campth use and 6 months following Campath therapy
Side Effects:-
Infusion related A/E: 6% discontinue Campath d/t infusion related A/E
Rigors, drug fever, nausea, vomiting, hypotension, rash, fatigue, urticaria,
Dyspnea, pruritus, headache, diarrhoea.
Infection: 43% risk despite PCP/Herpes prophylaxis (1/3 of pt Grade ¾ severity)
Hematological: Pancytopenia, marrow hypoplasia, Anemia, cytopenias, ITP
Dosing:
Campath therapy should be initiated at a dose of 3 mg administered as a 2 hour IV infusion daily.
When the Campath 3 mg daily dose is tolerated (e.g.infusion-related toxicities are ≤ Grade 2), the daily dose should be escalated to 10 mg and continued until tolerated.
When the 10 mg dose is tolerated, the maintenance dose of Campath 30 mg may be initiated.
The maintenance dose of Campath is 30 mg/day administered three 3 times per week on alternate days (i.e., Monday, Wednesday, and Friday) for up to 12 weeks.
In most patients, escalation to 30 mg can be accomplished in 3 - 7 days.
Dose escalation to the recommended maintenance dose of 30 mg administered three times per week is required.
Single doses of Campath greater than 30 mg or cumulative weekly doses of greater than 90 mg should not be administered since higher doses are associated with an increased incidence of pancytopenia.
Campath should be administered intravenously only.
The infusion should be administered over a 2 hour period.
DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.
Recommended Concomitant Medications:
Diphenhydramine 50 mg and acetaminophen 650 mg administered 30 minutes prior to Campath infusion.
In cases where severe infusion-related events occur, treatment with hydrocortisone 200 mg was used in decreasing the infusion-related events.
Patients should receive anti-infective prophylaxis to minimize the risks of serious opportunistic infections.
trimethoprim/sulfamethoxazole DS twice daily (BID) three times per week and famciclovir or 348 equivalent 250 mg twice a day (BID) upon initiation of Campath therapy.
Prophylaxis should be continued for 2 months after completion of Campath therapy or until the CD4+ count is ≥ 350
Campath therapy should be discontinued during serious infection, serious hematologic toxicity, or other serious toxicity until the event resolves.
Campath therapy should be permanently discontinued if evidence of autoimmune anemia or thrombocytopenia appears.
Dose is adjusted to Figure above
Preparation:
Aseptic technique should be used.
Withdraw the necessary amount of Campath from the ampoule into a syringe.
Filter with a sterile, low-protein binding, non-fiber releasing 5 μm filter prior to dilution.
Inject into 100 mL sterile 0.9% Sodium Chloride USP or 5% Dextrose in Water USP. Gently invert the bag to mix the solution.
Campath should be used within 8 hours after dilution.
Campath solutions may be stored at room temperature (15-30°C) or refrigerated.
Campath solutions should be protected from light.
Sunday, November 30, 2008
IV pulse cyclophosphamide for vasculitis- Addenbrooke's Hospital
CYC is given as intravenous pulses at weeks 0, 2, 4 and then every 3 weeks until the remission is reached at 3 - 6 months from start of therapy (max 10 doses min 6).
a) CYC may be stopped from 3 months onward provided patient in remission (BVAS 0 for 2 consecutive study assessments). After completion of CYC, AZA to be commenced.
b) Reductions for renal function and age according to table above.
c) Maximum CYC pulse is 1.2g.
d) Upon completion of CYC course AZA to be commenced.
e) Dissolve CYC in water for injection, then dilute in saline 0.9% 500 ml and administer as IV infusion over one hour.
f) Mesna is optional and will be administered orally in the same dose in mg as CYC in mg either from IV vials or in the form of tablets on days when CYC is administered. (If it has to be administered IV reduce mesna dose to 60% of the CYC dose).
g) Prevention of emesis: the choice of antiemetic drugs to cover the CYC pulses should follow local practice. Ondansetron is suitable for this indication.
h)Check FBC on day of pulse or previous day.
If WBC prior to pulse < 4 x 109/L, then postpone pulse until WBC > 4 x 109/L, while checking WBC at least weekly. Reduce dose of pulse by 25%. With any further episodes of leucopenia, make equivalent dose reduction.
i) Check FBC between days 10 and 14 after a pulse. If the leucocyte nadir (i.e. the lowest leucocyte count between two CYC pulses) is < 3 x 109/L, even if the WBC just previous to the next pulse is > 4 x 109/L, then reduce the dose of the next pulse by:
j) leucocyte nadir 1 - 2 x 109/L reduce CYC dose of last pulse by 40 % of previous dose.
k) leucocyte nadir 2 - 3 x 109/L reduce CYC dose of last pulse by 20 % of previous dose.
l) If in remission by three months, or between three and six months, may switch to AZA 2mg/kg/day.
Saturday, November 29, 2008
Etanercept- from uptodate
Etanercept: Drug information
SPECIAL ALERTS
Tumor Necrosis Factor (TNF) Blockers and Malignancy Risk - June 5, 2008
The U.S. Food and Drug Administration (FDA) issued an Early Communication to healthcare professionals regarding a possible association between TNF blocker (adalimumab, certolizumb pegol, etanercept, and infliximab) use and the development of malignancies in children and young adults. Over the last 10 years, the FDA has received ~30 reports of cancer in children or young adults who had been treated with TNF blockers prior to the age of 18 years. TNF blockers were given for the treatment of Juvenile Idiopathic Arthritis (JIA [formerly termed Juvenile Rheumatoid Arthritis]), Crohn's disease, or other indications in combination with other immunosuppressive medications (eg, azathioprine, 6-mercaptopurine or methotrexate). Approximately half of the reported cancers were lymphomas (Hodgkin's and non-Hodgkin's), which are cancers involving the cells of the immune system.
TNF blockers work by suppressing the immune system. The prescribing information for each TNF blocker contains warnings regarding the possible association of malignancy development with use. Malignancies may not be detected in short-term studies; long-term studies are necessary to identify the impact of TNF blocker therapy on malignancy development. The manufacturers of the four TNF blockers available in the U.S. are being asked by the FDA to provide information regarding all cases of cancer reported in children taking TNF blockers. The FDA is expected to report its findings in approximately 6 months, after completing a safety review and evaluation.
Additional information is available at http://www.fda.gov/medwatch/safety/2008/safety08.htm#TNF
Etanercept (Enbrel®): Revised Prescribing Information With the Addition of a Boxed Warning Concerning the Risk of Infection, Including Tuberculosis - May 2008
These product labeling changes have previously been incorporated into the etanercept Lexi-Comp monograph.
The FDA MedWatch alert can be found at: http://www.fda.gov/medwatch/safety/2008/safety08.htm#Enbrel
U.S. BRAND NAMES — Enbrel®
PHARMACOLOGIC CATEGORY
Antirheumatic, Disease Modifying
Tumor Necrosis Factor (TNF) Blocking Agent
DOSING: ADULTS
Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis: SubQ:
Once-weekly dosing: 50 mg once weekly
Twice-weekly dosing: 25 mg given twice weekly (individual doses should be separated by 72-96 hours)
Plaque psoriasis:
Initial: 50 mg twice weekly, 3-4 days apart (starting doses of 25 or 50 mg once weekly have also been used successfully); maintain initial dose for 3 months
Maintenance dose: 50 mg once weekly
DOSING: PEDIATRIC — Juvenile idiopathic arthritis: Children 2-17 years: SubQ:
(For additional information see "Etanercept: Pediatric drug information")
Once-weekly dosing: 0.8 mg/kg (maximum: 50 mg/dose) once weekly
Twice-weekly dosing: 0.4 mg/kg (maximum: 25 mg/dose) twice weekly (individual doses should be separated by 72-96 hours)
DOSING: ELDERLY — SubQ: Refer to adult dosing. Although greater sensitivity of some elderly patients cannot be ruled out, no overall differences in safety or effectiveness were observed.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution:
Enbrel®: 25 mg [contains sucrose 10 mg; diluent contains benzyl alcohol]
Injection, solution [preservative free]:
Enbrel®: 50 mg/mL (0.51 mL, 0.98 mL) [contains sucrose 1%; natural rubber/natural latex in packaging]
DOSAGE FORMS: CONCISE
Injection, powder for reconstitution:
Enbrel®: 25 mg
Injection, solution [preservative free]:
Enbrel®: 50 mg/mL (0.51 mL, 0.98 mL)
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Administer subcutaneously. Rotate injection sites. New injections should be given at least one inch from an old site and never into areas where the skin is tender, bruised, red, or hard. Note: If the physician determines that it is appropriate, patients may self-inject after proper training in injection technique.
Powder for reconstitution: Follow package instructions carefully for reconstitution. The maximum amount injected at any single site should not exceed 25 mg.
Solution for injection: May be allowed to reach room temperature prior to injection.
USE — Treatment of moderately- to severely-active rheumatoid arthritis (RA); moderately- to severely-active polyarticular juvenile idiopathic arthritis (JIA); psoriatic arthritis; active ankylosing spondylitis (AS); moderate-to-severe chronic plaque psoriasis
ADVERSE REACTIONS SIGNIFICANT — Percentages reported for adults except where specified.
>10%:
Central nervous system: Headache (17%; children 19%)
Gastrointestinal: Abdominal pain (5%; children 19%), vomiting (3%; children 13%)
Local: Injection site reaction (14% to 37%; erythema, itching, pain or swelling)
Respiratory: Respiratory tract infection (upper; 12% to 29%), rhinitis (12% to 16%)
Miscellaneous: Infection (35%; children 63%), positive ANA (11%), positive antidouble-stranded DNA antibodies (15% by RIA, 3% by Crithidia luciliae assay)
≥3% to 10%:
Cardiovascular: Edema (2% to 8%)
Central nervous system: Dizziness (7%)
Dermatologic: Rash (5%)
Gastrointestinal: Dyspepsia (4%), nausea (children 9%)
Neuromuscular & skeletal: Weakness (5%)
Respiratory: Pharyngitis (7%), respiratory disorder (5%), sinusitis (3%), cough (6%)
<3%, postmarketing, and/or case reports: Abscess, adenopathy, allergic reactions, alopecia, anemia, angioedema, anorexia, aplastic anemia, appendicitis, aseptic meningitis, bursitis, cerebral ischemia, chest pain, cholecystitis, coagulopathy; demyelinating CNS disorders (suggestive of multiple sclerosis, transverse myelitis, or optic neuritis); deep vein thrombosis, depression, diarrhea, dyspnea, erythema multiforme, fatigue, fever, flushing, flu-like syndrome, gastrointestinal hemorrhage, heart failure, hepatitis (autoimmune), hydrocephalus (with normal pressure), hyper-/hypotension; infections (bacterial, fungal, protozoal, viral); interstitial lung disease, intestinal perforation, joint pain, leukopenia, lupus-like syndrome, lymphadenopathy, malignancies (including lymphoma), membranous glomerulopathy, MI, mouth ulcer, multiple sclerosis, myocardial ischemia, neutropenia, ocular inflammation, optic neuritis, pancytopenia, pancreatitis, paresthesia, polymyositis, pruritus, psoriasis exacerbation, pulmonary disease, pulmonary embolism, renal calculus, sarcoidosis, seizure, stroke, Stevens-Johnson syndrome, subcutaneous nodules, taste disturbances, thrombocytopenia, thrombophlebitis, toxic epidermal necrolysis, transaminases increased, tuberculosis, tuberculous arthritis, urinary tract infection, urticaria, vasculitis (cutaneous), weight gain, xerophthalmia, xerostomia
CONTRAINDICATIONS — Hypersensitivity to etanercept or any component of the formulation; patients with sepsis (mortality may be increased); active infections (including chronic or local infection)
WARNINGS / PRECAUTIONS
Boxed warnings:
* Infections: See "Concerns related to adverse effects" below.
* Tuberculosis: See "Concerns related to adverse effects" below.
Concerns related to adverse effects:
* Anaphylaxis/hypersensitivity reactions: Allergic reactions may occur, but anaphylaxis has not been observed. If an anaphylactic reaction or other serious allergic reaction occurs, administration should be discontinued immediately and appropriate therapy initiated.
* Autoimmune disorder: Positive antinuclear antibody titers have been detected in patients (with negative baselines). Rare cases of autoimmune disorder, including lupus-like syndrome or autoimmune hepatitis, have been reported; monitor and discontinue if symptoms develop.
* Hepatitis B: Rare reactivation of hepatitis B has occurred in chronic carriers of the virus; evaluate prior to initiation and during treatment in patients at risk for hepatitis B infection.
* Infections: [U.S. Boxed Warning]: Serious and potentially fatal infections have been reported including bacterial sepsis and tuberculosis. Discontinue administration if patient develops a serious infection or sepsis. Caution should be exercised when considering the use in patients with chronic infection, history of recurrent infection, or predisposition to infection (such as poorly-controlled diabetes). Do not give to patients with an active chronic or localized infection. Patients should be educated about the symptoms of infection and closely monitored for signs and symptoms while undergoing treatment.
* Malignancy: Use may affect defenses against malignancies; impact on the development and course of malignancies is not fully defined. As compared to the general population, an increased risk of lymphoma has been noted in clinical trials; however, rheumatoid arthritis has been previously associated with an increased rate of lymphoma.
* Tuberculosis: [U.S. Boxed Warning]: Tuberculosis (disseminated or extrapulmonary) has been reported in patients receiving etanercept; both reactivation of latent infection and new infections have been reported. Patients should be evaluated for latent tuberculosis infection with a tuberculin skin test prior to starting therapy. Treatment of latent tuberculosis should be initiated before therapy is used. Some patients who tested negative prior to therapy have developed active infection; monitor for signs and symptoms of tuberculosis in all patients.
Disease-related concerns:
* Demyelinating CNS disease: Use with caution in patients with pre-existing or recent onset CNS demyelinating disorders; rare cases of new onset or exacerbation of CNS demyelinating disorders have occurred; may present with mental status changes and some may be associated with permanent disability. Optic neuritis, transverse myelitis, multiple sclerosis, and new onset or exacerbation of seizures have been reported.
* Heart failure: Use with caution in patients with heart failure or decreased left ventricular function; worsening and new-onset heart failure has been reported.
* Hematologic disorders: Use with caution in patients with a history of significant hematologic abnormalities; has been associated with pancytopenia and aplastic anemia (rare cases in postmarketing experience). Patients must be advised to seek medical attention if they develop signs and symptoms suggestive of blood dyscrasias; discontinue if significant hematologic abnormalities are confirmed.
* Wegener's granulomatosis: Use is not recommended for use in patients with Wegener's granulomatosis who are receiving immunosuppressive therapy due to higher incidence of noncutaneous solid malignancies.
Concurrent drug therapy issues:
* Anakinra: Due to higher incidence of serious infections, should not be used in combination with anakinra unless no satisfactory alternatives exist, and then only with extreme caution.
Special populations:
* Pediatrics: Safety and efficacy have not been established in children <2 years of age.
* Varicella virus exposure: Patients with a significant exposure to varicella virus should temporarily discontinue therapy; treatment with varicella zoster immune globulin should be considered.
Dosage form specific issues:
* Latex: Some dosage forms may contain dry natural rubber (latex).
Other warnings/precautions:
* Immunizations: Patients should be brought up to date with all immunizations before initiating therapy. Live vaccines should not be given concurrently; there is no data available concerning secondary transmission of live vaccines in patients receiving therapy.
RESTRICTIONS
An FDA-approved patient medication guide is available and must be distributed when dispensing an outpatient prescription (new or refill) where this medication is to be used without direct supervision of a healthcare provider. Medication guides are available at http://www.fda.gov/cder/Offices/ODS/medication_guides.htm.
DRUG INTERACTIONS
Abatacept: Anti-TNF Agents may enhance the adverse/toxic effect of Abatacept. An increased risk of serious infection during concomitant use has been reported. Risk D: Consider therapy modification
(For additional information: Launch Lexi-Interact™ Drug Interactions Program )
Anakinra: Anti-TNF Agents may enhance the adverse/toxic effect of Anakinra. An increased risk of serious infection during concomitant use has been reported. Risk X: Avoid combination
Cyclophosphamide: Etanercept may enhance the adverse/toxic effect of Cyclophosphamide. An increased risk of solid cancer development may be present. Risk D: Consider therapy modification
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinal infections may develop. Immunosuppressants may also decrease therapeutic response to vaccines. Risk X: Avoid combination
ETHANOL / NUTRITION / HERB INTERACTIONS — Herb/Nutraceutical: Echinacea may decrease the therapeutic effects of etanercept (avoid concurrent use).
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Developmental toxicity studies performed in animals have revealed no evidence of harm to the fetus. There are no studies in pregnant women; this drug should be used during pregnancy only if clearly needed. A pregnancy registry has been established to monitor outcomes of women exposed to etanercept during pregnancy (877-311-8972).
LACTATION — Excretion in breast milk unknown/not recommended
BREAST-FEEDING CONSIDERATIONS — It is not known whether etanercept is excreted in human milk. Because many immunoglobulins are excreted in human milk and the potential for serious adverse reactions exists, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
PRICING — (data from drugstore.com)
Kit (Enbrel)
25 mg (4): $748.92
Solution (Enbrel)
50 mg/mL (3.92): $1471.69
Solution (Enbrel SureClick)
50 mg/mL (3.92): $1541.98
MONITORING PARAMETERS
Signs and symptoms of infection (prior to and during therapy); latent TB screening prior to therapy initiation
CANADIAN BRAND NAMES — Enbrel®
INTERNATIONAL BRAND NAMES — Enbrel (AR, AT, AU, BE, BG, BR, CH, CN, CO, CR, CZ, DE, DK, ES, FI, FR, GB, GR, GT, HK, HN, IE, IL, IN, IT, KP, MX, MY, NI, NL, NO, PA, PE, PH, PL, PT, RU, SE, SG, SV, TH, TR, VE)
MECHANISM OF ACTION — Etanercept is a recombinant DNA-derived protein composed of tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. Etanercept binds tumor necrosis factor (TNF) and blocks its interaction with cell surface receptors. TNF plays an important role in the inflammatory processes and the resulting joint pathology of rheumatoid arthritis (RA), polyarticular-course juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), and plaque psoriasis.
PHARMACODYNAMICS / KINETICS
Onset of action: ~2-3 weeks; RA: 1-2 weeks
Half-life elimination: RA: SubQ: 72-132 hours
Time to peak: RA: SubQ: 35-103 hours
Excretion: Clearance: Children: 45.9 mL/hour/m2; Adults: 89 mL/hour (52 mL/hour/m2)
PATIENT INFORMATION — If self-injecting, follow instructions for injection and disposal of needles exactly. If redness, swelling, or irritation appears at the injection site, contact prescriber. Do not have any vaccinations while using this medication without consulting prescriber first. You may experience headache or dizziness (use caution when driving or engaging in tasks requiring alertness until response to drug is known). If stomach pain or cramping, unusual bleeding or bruising, persistent fever, paleness, blood in vomitus, stool, or urine occurs, stop taking medication and contact prescriber immediately. Also immediately report skin rash, unusual muscle or bone weakness, or signs of respiratory flu or other infection (eg, chills, fever, sore throat, easy bruising or bleeding, mouth sores, unhealed sores).
SPECIAL ALERTS
Tumor Necrosis Factor (TNF) Blockers and Malignancy Risk - June 5, 2008
The U.S. Food and Drug Administration (FDA) issued an Early Communication to healthcare professionals regarding a possible association between TNF blocker (adalimumab, certolizumb pegol, etanercept, and infliximab) use and the development of malignancies in children and young adults. Over the last 10 years, the FDA has received ~30 reports of cancer in children or young adults who had been treated with TNF blockers prior to the age of 18 years. TNF blockers were given for the treatment of Juvenile Idiopathic Arthritis (JIA [formerly termed Juvenile Rheumatoid Arthritis]), Crohn's disease, or other indications in combination with other immunosuppressive medications (eg, azathioprine, 6-mercaptopurine or methotrexate). Approximately half of the reported cancers were lymphomas (Hodgkin's and non-Hodgkin's), which are cancers involving the cells of the immune system.
TNF blockers work by suppressing the immune system. The prescribing information for each TNF blocker contains warnings regarding the possible association of malignancy development with use. Malignancies may not be detected in short-term studies; long-term studies are necessary to identify the impact of TNF blocker therapy on malignancy development. The manufacturers of the four TNF blockers available in the U.S. are being asked by the FDA to provide information regarding all cases of cancer reported in children taking TNF blockers. The FDA is expected to report its findings in approximately 6 months, after completing a safety review and evaluation.
Additional information is available at http://www.fda.gov/medwatch/safety/2008/safety08.htm#TNF
Etanercept (Enbrel®): Revised Prescribing Information With the Addition of a Boxed Warning Concerning the Risk of Infection, Including Tuberculosis - May 2008
These product labeling changes have previously been incorporated into the etanercept Lexi-Comp monograph.
The FDA MedWatch alert can be found at: http://www.fda.gov/medwatch/safety/2008/safety08.htm#Enbrel
U.S. BRAND NAMES — Enbrel®
PHARMACOLOGIC CATEGORY
Antirheumatic, Disease Modifying
Tumor Necrosis Factor (TNF) Blocking Agent
DOSING: ADULTS
Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis: SubQ:
Once-weekly dosing: 50 mg once weekly
Twice-weekly dosing: 25 mg given twice weekly (individual doses should be separated by 72-96 hours)
Plaque psoriasis:
Initial: 50 mg twice weekly, 3-4 days apart (starting doses of 25 or 50 mg once weekly have also been used successfully); maintain initial dose for 3 months
Maintenance dose: 50 mg once weekly
DOSING: PEDIATRIC — Juvenile idiopathic arthritis: Children 2-17 years: SubQ:
(For additional information see "Etanercept: Pediatric drug information")
Once-weekly dosing: 0.8 mg/kg (maximum: 50 mg/dose) once weekly
Twice-weekly dosing: 0.4 mg/kg (maximum: 25 mg/dose) twice weekly (individual doses should be separated by 72-96 hours)
DOSING: ELDERLY — SubQ: Refer to adult dosing. Although greater sensitivity of some elderly patients cannot be ruled out, no overall differences in safety or effectiveness were observed.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution:
Enbrel®: 25 mg [contains sucrose 10 mg; diluent contains benzyl alcohol]
Injection, solution [preservative free]:
Enbrel®: 50 mg/mL (0.51 mL, 0.98 mL) [contains sucrose 1%; natural rubber/natural latex in packaging]
DOSAGE FORMS: CONCISE
Injection, powder for reconstitution:
Enbrel®: 25 mg
Injection, solution [preservative free]:
Enbrel®: 50 mg/mL (0.51 mL, 0.98 mL)
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Administer subcutaneously. Rotate injection sites. New injections should be given at least one inch from an old site and never into areas where the skin is tender, bruised, red, or hard. Note: If the physician determines that it is appropriate, patients may self-inject after proper training in injection technique.
Powder for reconstitution: Follow package instructions carefully for reconstitution. The maximum amount injected at any single site should not exceed 25 mg.
Solution for injection: May be allowed to reach room temperature prior to injection.
USE — Treatment of moderately- to severely-active rheumatoid arthritis (RA); moderately- to severely-active polyarticular juvenile idiopathic arthritis (JIA); psoriatic arthritis; active ankylosing spondylitis (AS); moderate-to-severe chronic plaque psoriasis
ADVERSE REACTIONS SIGNIFICANT — Percentages reported for adults except where specified.
>10%:
Central nervous system: Headache (17%; children 19%)
Gastrointestinal: Abdominal pain (5%; children 19%), vomiting (3%; children 13%)
Local: Injection site reaction (14% to 37%; erythema, itching, pain or swelling)
Respiratory: Respiratory tract infection (upper; 12% to 29%), rhinitis (12% to 16%)
Miscellaneous: Infection (35%; children 63%), positive ANA (11%), positive antidouble-stranded DNA antibodies (15% by RIA, 3% by Crithidia luciliae assay)
≥3% to 10%:
Cardiovascular: Edema (2% to 8%)
Central nervous system: Dizziness (7%)
Dermatologic: Rash (5%)
Gastrointestinal: Dyspepsia (4%), nausea (children 9%)
Neuromuscular & skeletal: Weakness (5%)
Respiratory: Pharyngitis (7%), respiratory disorder (5%), sinusitis (3%), cough (6%)
<3%, postmarketing, and/or case reports: Abscess, adenopathy, allergic reactions, alopecia, anemia, angioedema, anorexia, aplastic anemia, appendicitis, aseptic meningitis, bursitis, cerebral ischemia, chest pain, cholecystitis, coagulopathy; demyelinating CNS disorders (suggestive of multiple sclerosis, transverse myelitis, or optic neuritis); deep vein thrombosis, depression, diarrhea, dyspnea, erythema multiforme, fatigue, fever, flushing, flu-like syndrome, gastrointestinal hemorrhage, heart failure, hepatitis (autoimmune), hydrocephalus (with normal pressure), hyper-/hypotension; infections (bacterial, fungal, protozoal, viral); interstitial lung disease, intestinal perforation, joint pain, leukopenia, lupus-like syndrome, lymphadenopathy, malignancies (including lymphoma), membranous glomerulopathy, MI, mouth ulcer, multiple sclerosis, myocardial ischemia, neutropenia, ocular inflammation, optic neuritis, pancytopenia, pancreatitis, paresthesia, polymyositis, pruritus, psoriasis exacerbation, pulmonary disease, pulmonary embolism, renal calculus, sarcoidosis, seizure, stroke, Stevens-Johnson syndrome, subcutaneous nodules, taste disturbances, thrombocytopenia, thrombophlebitis, toxic epidermal necrolysis, transaminases increased, tuberculosis, tuberculous arthritis, urinary tract infection, urticaria, vasculitis (cutaneous), weight gain, xerophthalmia, xerostomia
CONTRAINDICATIONS — Hypersensitivity to etanercept or any component of the formulation; patients with sepsis (mortality may be increased); active infections (including chronic or local infection)
WARNINGS / PRECAUTIONS
Boxed warnings:
* Infections: See "Concerns related to adverse effects" below.
* Tuberculosis: See "Concerns related to adverse effects" below.
Concerns related to adverse effects:
* Anaphylaxis/hypersensitivity reactions: Allergic reactions may occur, but anaphylaxis has not been observed. If an anaphylactic reaction or other serious allergic reaction occurs, administration should be discontinued immediately and appropriate therapy initiated.
* Autoimmune disorder: Positive antinuclear antibody titers have been detected in patients (with negative baselines). Rare cases of autoimmune disorder, including lupus-like syndrome or autoimmune hepatitis, have been reported; monitor and discontinue if symptoms develop.
* Hepatitis B: Rare reactivation of hepatitis B has occurred in chronic carriers of the virus; evaluate prior to initiation and during treatment in patients at risk for hepatitis B infection.
* Infections: [U.S. Boxed Warning]: Serious and potentially fatal infections have been reported including bacterial sepsis and tuberculosis. Discontinue administration if patient develops a serious infection or sepsis. Caution should be exercised when considering the use in patients with chronic infection, history of recurrent infection, or predisposition to infection (such as poorly-controlled diabetes). Do not give to patients with an active chronic or localized infection. Patients should be educated about the symptoms of infection and closely monitored for signs and symptoms while undergoing treatment.
* Malignancy: Use may affect defenses against malignancies; impact on the development and course of malignancies is not fully defined. As compared to the general population, an increased risk of lymphoma has been noted in clinical trials; however, rheumatoid arthritis has been previously associated with an increased rate of lymphoma.
* Tuberculosis: [U.S. Boxed Warning]: Tuberculosis (disseminated or extrapulmonary) has been reported in patients receiving etanercept; both reactivation of latent infection and new infections have been reported. Patients should be evaluated for latent tuberculosis infection with a tuberculin skin test prior to starting therapy. Treatment of latent tuberculosis should be initiated before therapy is used. Some patients who tested negative prior to therapy have developed active infection; monitor for signs and symptoms of tuberculosis in all patients.
Disease-related concerns:
* Demyelinating CNS disease: Use with caution in patients with pre-existing or recent onset CNS demyelinating disorders; rare cases of new onset or exacerbation of CNS demyelinating disorders have occurred; may present with mental status changes and some may be associated with permanent disability. Optic neuritis, transverse myelitis, multiple sclerosis, and new onset or exacerbation of seizures have been reported.
* Heart failure: Use with caution in patients with heart failure or decreased left ventricular function; worsening and new-onset heart failure has been reported.
* Hematologic disorders: Use with caution in patients with a history of significant hematologic abnormalities; has been associated with pancytopenia and aplastic anemia (rare cases in postmarketing experience). Patients must be advised to seek medical attention if they develop signs and symptoms suggestive of blood dyscrasias; discontinue if significant hematologic abnormalities are confirmed.
* Wegener's granulomatosis: Use is not recommended for use in patients with Wegener's granulomatosis who are receiving immunosuppressive therapy due to higher incidence of noncutaneous solid malignancies.
Concurrent drug therapy issues:
* Anakinra: Due to higher incidence of serious infections, should not be used in combination with anakinra unless no satisfactory alternatives exist, and then only with extreme caution.
Special populations:
* Pediatrics: Safety and efficacy have not been established in children <2 years of age.
* Varicella virus exposure: Patients with a significant exposure to varicella virus should temporarily discontinue therapy; treatment with varicella zoster immune globulin should be considered.
Dosage form specific issues:
* Latex: Some dosage forms may contain dry natural rubber (latex).
Other warnings/precautions:
* Immunizations: Patients should be brought up to date with all immunizations before initiating therapy. Live vaccines should not be given concurrently; there is no data available concerning secondary transmission of live vaccines in patients receiving therapy.
RESTRICTIONS
An FDA-approved patient medication guide is available and must be distributed when dispensing an outpatient prescription (new or refill) where this medication is to be used without direct supervision of a healthcare provider. Medication guides are available at http://www.fda.gov/cder/Offices/ODS/medication_guides.htm.
DRUG INTERACTIONS
Abatacept: Anti-TNF Agents may enhance the adverse/toxic effect of Abatacept. An increased risk of serious infection during concomitant use has been reported. Risk D: Consider therapy modification
(For additional information: Launch Lexi-Interact™ Drug Interactions Program )
Anakinra: Anti-TNF Agents may enhance the adverse/toxic effect of Anakinra. An increased risk of serious infection during concomitant use has been reported. Risk X: Avoid combination
Cyclophosphamide: Etanercept may enhance the adverse/toxic effect of Cyclophosphamide. An increased risk of solid cancer development may be present. Risk D: Consider therapy modification
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinal infections may develop. Immunosuppressants may also decrease therapeutic response to vaccines. Risk X: Avoid combination
ETHANOL / NUTRITION / HERB INTERACTIONS — Herb/Nutraceutical: Echinacea may decrease the therapeutic effects of etanercept (avoid concurrent use).
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Developmental toxicity studies performed in animals have revealed no evidence of harm to the fetus. There are no studies in pregnant women; this drug should be used during pregnancy only if clearly needed. A pregnancy registry has been established to monitor outcomes of women exposed to etanercept during pregnancy (877-311-8972).
LACTATION — Excretion in breast milk unknown/not recommended
BREAST-FEEDING CONSIDERATIONS — It is not known whether etanercept is excreted in human milk. Because many immunoglobulins are excreted in human milk and the potential for serious adverse reactions exists, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
PRICING — (data from drugstore.com)
Kit (Enbrel)
25 mg (4): $748.92
Solution (Enbrel)
50 mg/mL (3.92): $1471.69
Solution (Enbrel SureClick)
50 mg/mL (3.92): $1541.98
MONITORING PARAMETERS
Signs and symptoms of infection (prior to and during therapy); latent TB screening prior to therapy initiation
CANADIAN BRAND NAMES — Enbrel®
INTERNATIONAL BRAND NAMES — Enbrel (AR, AT, AU, BE, BG, BR, CH, CN, CO, CR, CZ, DE, DK, ES, FI, FR, GB, GR, GT, HK, HN, IE, IL, IN, IT, KP, MX, MY, NI, NL, NO, PA, PE, PH, PL, PT, RU, SE, SG, SV, TH, TR, VE)
MECHANISM OF ACTION — Etanercept is a recombinant DNA-derived protein composed of tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. Etanercept binds tumor necrosis factor (TNF) and blocks its interaction with cell surface receptors. TNF plays an important role in the inflammatory processes and the resulting joint pathology of rheumatoid arthritis (RA), polyarticular-course juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), and plaque psoriasis.
PHARMACODYNAMICS / KINETICS
Onset of action: ~2-3 weeks; RA: 1-2 weeks
Half-life elimination: RA: SubQ: 72-132 hours
Time to peak: RA: SubQ: 35-103 hours
Excretion: Clearance: Children: 45.9 mL/hour/m2; Adults: 89 mL/hour (52 mL/hour/m2)
PATIENT INFORMATION — If self-injecting, follow instructions for injection and disposal of needles exactly. If redness, swelling, or irritation appears at the injection site, contact prescriber. Do not have any vaccinations while using this medication without consulting prescriber first. You may experience headache or dizziness (use caution when driving or engaging in tasks requiring alertness until response to drug is known). If stomach pain or cramping, unusual bleeding or bruising, persistent fever, paleness, blood in vomitus, stool, or urine occurs, stop taking medication and contact prescriber immediately. Also immediately report skin rash, unusual muscle or bone weakness, or signs of respiratory flu or other infection (eg, chills, fever, sore throat, easy bruising or bleeding, mouth sores, unhealed sores).
Infliximab administration protocol
Protocol for Infliximab Infusion (Adults)
Indications and Dosage:
Rheumatoid arthritis, used in combination with methotrexate, where response to at least two DMARDS has been inadequate (NICE guidance).
• 3mg/kg IV infusion, followed by additional 3mg/kg at weeks 0, 2 and 6 weeks, then every 8 weeks depending on response/need. Clinical response is usually achieved within 12 weeks. Continued therapy should be reconsidered in patients who show no evidence of therapeutic benefit within this time.
Severe, active Crohn’s disease – treatment of severe, active disease in patients who have not responded despite a full and adequate course of therapy with a corticosteroid or immunosuppressant; or who are intolerant or have medical contraindications for such therapies.
• 5mg/kg IV infusion at 0, 2 and 6 weeks. In patients who respond alternative strategies for continued treatment are: • Maintenance: repeat infusions of 5mg/kg every 8 weeks depending on response/need or • Readministration: 5mg/kg infusion if signs and symptoms recur within 16 weeks of last infusion
Fistulising, active Crohn’s disease - treatment of fistulising, active Crohn’s disease, in patients who have not responded, despite full and adequate course of conventional treatment.
• initial 5mg/kg IV infusion, followed with additional 5mg/kg infusion doses at 2 and 6 weeks after the first infusion. If a patient does not respond after 3 doses, no additional treatment with infliximab should be given. In patients who respond alternative strategies for continued treatment are: • Additional infusions of 5mg/kg every 8 weeks or • Readministration if signs and symptoms of the disease recur within 16 weeks of last infusion followed by infusions of 5mg/kg every 8 weeks.
Ulcerative colitis - treatment of moderately to severely active ulcerative colitis in patients who have had an inadequate response to conventional therapy including corticosteroids and 6-mercaptopurine or azathioprine, or who are intolerant to or have medical contraindications for such therapies.
• 5 mg/kg given as an intravenous infusion over a 2 hour period followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. • Clinical response is usually achieved within 14 weeks of treatment, i.e. three doses. • Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within this time period.
Ankylosing spondylitis – in patients who have severe axial symptoms, elevated serological markers of inflammatory activity and who have responded inadequately to conventional therapy.
• 5mg/kg IV infusion followed by additional 5mg/kg infusion at 2 and 6 weeks after the first infusion, then every 6-8 weeks depending on response/need thereafter. If a patient does not respond by 6 weeks (ie after 2 doses), no additional treatment with infliximab should be given.
Psoriatic arthritis, in combination with methotrexate, for treatment of active and progressive psoriatic arthritis in patients who have responded inadequately to DMARDs. • 5mg/kg IV infusion followed by 5mg/kg infusion at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter depending on response/need.
Pretreatment:
Patients should be supplied with the package leaflet and special Alert card.
Contraindications:
• patients with TB or other severe infections such as sepsis, abcesses and opportunistic infections
• patients with moderate of severe heart failure
• hypersensitivity to infliximab, other murine proteins or any of the excipients
Special Warnings and Precautions for Use:
Infusion reactions • Associated with acute infusion-related reactions (eg wheezing, hypotension, pallor, nausea, anaphylactic shock and delayed hypersensitivity) which may develop within seconds or within a few hours following infusion. If this occurs then stop infusion immediately and refer to doctor.
• For severe reactions patients may require treatment with IV hydrocortisone, nebulised salbutamol and chlorphenamine.
• For mild reactions (including: drop in systolic BP < 40mmHg normal blood pressure) the infusion should be temporarily stopped until symptoms subside. Following discussion with a doctor the infusion may be restarted at a slower rate. Some patients may be rechallenged after several weeks.
• Hydrocortisone and/or paracetamol 30 mins before infliximab can prevent mild and transient effects. Infections
• Monitor closely for infections, including TB, before, during and up to 6 months after treatment
When to Withold Treatment
• Presentation of signs and symptoms of intercurrent infection. This includes upper respiratory tract infection and skin ulcer.
• Worsening of coexisting illness such as CCF or diabetes
• Suspected malignancy
• Persistent hypotension (systolic < 100mmHg)
• Impending Surgery (4 week gap for standard procedures; 8 week gap for high sepsis- risk surgery) – restart after wound healing
Exclude Infection Prior to Each Administration:
• Take a complete history and examination
• Monitor: • temperature, • urinalysis – refer to doctor if positive for blood or protein
• Send for the following bloodtests: FBC, ESR, U&Es, LFTs, CRP
• Additional tests for RA patients: Rheumatoid factor, ANA-dsDNA
Administration and Monitoring:
• Infliximab is obtained from the Aseptic Dispensing Unit (ADU), Pharmacy.
24 hour notice is required.
• IV Hydrocortisone 100-200mg stat prior to infliximab - not always necessary, there is evidence to suggest that this reduces the incidence of infliximab antibodies. Check with the prescriber.
• Insert venflon and flush with normal saline.
Monitor blood pressure, pulse and temperature every 30 minutes during the infusion and observation periods.
Patients should be observed for at least 1-2 hours post infusion for acute infusion related reactions.
• Infliximab is given in 250ml of sodium chloride 0.9%, and should be infused over a 2 hour period.
Occasionally there are patient specific deviations from this regimen.
The drug can be given through a normal giving set, via a 1.2-micron low-protein binding filter.
Filters can be ordered from supplies: "1.2micron filter lipid solutions priming volume 0.2cc male/female connectors" Medex code MX1483 Supplier = NHS Logistics, code FTC192 Rheumatoid arthritis patients – for carefully selected patients who have received 3 initial infusions over a 2 hour period, subsequent infusions can be infused over a period of not less than 1 hour, and patients observed for 1 hour afterwards.
Side Effects and Toxicity:
Recognised side effects of treatment include flu-like symptoms, headache, transient fever, gastrointestinal upset and skin rashes. Please consult the infliximab data sheet available on-line at www.medicines.org.uk for a complete list. Rarely patients have become ANA positive and developed lupus-like syndromes while receiving treatment. Adverse reactions should be reported to the CSM using the “Yellow Cards” in the usual manner.
Indications and Dosage:
Rheumatoid arthritis, used in combination with methotrexate, where response to at least two DMARDS has been inadequate (NICE guidance).
• 3mg/kg IV infusion, followed by additional 3mg/kg at weeks 0, 2 and 6 weeks, then every 8 weeks depending on response/need. Clinical response is usually achieved within 12 weeks. Continued therapy should be reconsidered in patients who show no evidence of therapeutic benefit within this time.
Severe, active Crohn’s disease – treatment of severe, active disease in patients who have not responded despite a full and adequate course of therapy with a corticosteroid or immunosuppressant; or who are intolerant or have medical contraindications for such therapies.
• 5mg/kg IV infusion at 0, 2 and 6 weeks. In patients who respond alternative strategies for continued treatment are: • Maintenance: repeat infusions of 5mg/kg every 8 weeks depending on response/need or • Readministration: 5mg/kg infusion if signs and symptoms recur within 16 weeks of last infusion
Fistulising, active Crohn’s disease - treatment of fistulising, active Crohn’s disease, in patients who have not responded, despite full and adequate course of conventional treatment.
• initial 5mg/kg IV infusion, followed with additional 5mg/kg infusion doses at 2 and 6 weeks after the first infusion. If a patient does not respond after 3 doses, no additional treatment with infliximab should be given. In patients who respond alternative strategies for continued treatment are: • Additional infusions of 5mg/kg every 8 weeks or • Readministration if signs and symptoms of the disease recur within 16 weeks of last infusion followed by infusions of 5mg/kg every 8 weeks.
Ulcerative colitis - treatment of moderately to severely active ulcerative colitis in patients who have had an inadequate response to conventional therapy including corticosteroids and 6-mercaptopurine or azathioprine, or who are intolerant to or have medical contraindications for such therapies.
• 5 mg/kg given as an intravenous infusion over a 2 hour period followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. • Clinical response is usually achieved within 14 weeks of treatment, i.e. three doses. • Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within this time period.
Ankylosing spondylitis – in patients who have severe axial symptoms, elevated serological markers of inflammatory activity and who have responded inadequately to conventional therapy.
• 5mg/kg IV infusion followed by additional 5mg/kg infusion at 2 and 6 weeks after the first infusion, then every 6-8 weeks depending on response/need thereafter. If a patient does not respond by 6 weeks (ie after 2 doses), no additional treatment with infliximab should be given.
Psoriatic arthritis, in combination with methotrexate, for treatment of active and progressive psoriatic arthritis in patients who have responded inadequately to DMARDs. • 5mg/kg IV infusion followed by 5mg/kg infusion at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter depending on response/need.
Pretreatment:
Patients should be supplied with the package leaflet and special Alert card.
Contraindications:
• patients with TB or other severe infections such as sepsis, abcesses and opportunistic infections
• patients with moderate of severe heart failure
• hypersensitivity to infliximab, other murine proteins or any of the excipients
Special Warnings and Precautions for Use:
Infusion reactions • Associated with acute infusion-related reactions (eg wheezing, hypotension, pallor, nausea, anaphylactic shock and delayed hypersensitivity) which may develop within seconds or within a few hours following infusion. If this occurs then stop infusion immediately and refer to doctor.
• For severe reactions patients may require treatment with IV hydrocortisone, nebulised salbutamol and chlorphenamine.
• For mild reactions (including: drop in systolic BP < 40mmHg normal blood pressure) the infusion should be temporarily stopped until symptoms subside. Following discussion with a doctor the infusion may be restarted at a slower rate. Some patients may be rechallenged after several weeks.
• Hydrocortisone and/or paracetamol 30 mins before infliximab can prevent mild and transient effects. Infections
• Monitor closely for infections, including TB, before, during and up to 6 months after treatment
When to Withold Treatment
• Presentation of signs and symptoms of intercurrent infection. This includes upper respiratory tract infection and skin ulcer.
• Worsening of coexisting illness such as CCF or diabetes
• Suspected malignancy
• Persistent hypotension (systolic < 100mmHg)
• Impending Surgery (4 week gap for standard procedures; 8 week gap for high sepsis- risk surgery) – restart after wound healing
Exclude Infection Prior to Each Administration:
• Take a complete history and examination
• Monitor: • temperature, • urinalysis – refer to doctor if positive for blood or protein
• Send for the following bloodtests: FBC, ESR, U&Es, LFTs, CRP
• Additional tests for RA patients: Rheumatoid factor, ANA-dsDNA
Administration and Monitoring:
• Infliximab is obtained from the Aseptic Dispensing Unit (ADU), Pharmacy.
24 hour notice is required.
• IV Hydrocortisone 100-200mg stat prior to infliximab - not always necessary, there is evidence to suggest that this reduces the incidence of infliximab antibodies. Check with the prescriber.
• Insert venflon and flush with normal saline.
Monitor blood pressure, pulse and temperature every 30 minutes during the infusion and observation periods.
Patients should be observed for at least 1-2 hours post infusion for acute infusion related reactions.
• Infliximab is given in 250ml of sodium chloride 0.9%, and should be infused over a 2 hour period.
Occasionally there are patient specific deviations from this regimen.
The drug can be given through a normal giving set, via a 1.2-micron low-protein binding filter.
Filters can be ordered from supplies: "1.2micron filter lipid solutions priming volume 0.2cc male/female connectors" Medex code MX1483 Supplier = NHS Logistics, code FTC192 Rheumatoid arthritis patients – for carefully selected patients who have received 3 initial infusions over a 2 hour period, subsequent infusions can be infused over a period of not less than 1 hour, and patients observed for 1 hour afterwards.
Side Effects and Toxicity:
Recognised side effects of treatment include flu-like symptoms, headache, transient fever, gastrointestinal upset and skin rashes. Please consult the infliximab data sheet available on-line at www.medicines.org.uk for a complete list. Rarely patients have become ANA positive and developed lupus-like syndromes while receiving treatment. Adverse reactions should be reported to the CSM using the “Yellow Cards” in the usual manner.
Plasmapheresis Protocol- Hospital Kuala Lumpur
1-2 plasma volume/session
PV= (1-Hct)(b+cW)
Hct= Hematocrit
b=1530 for males, 864 for females
c=41 for males, 47.2 for females
W= lean body weight
Rough estimation: at Hct 45.
Plasma Volume=40ml/kg (BW)
Usually 5-7 sessions of plasmapheresis is required exchanges is usu done 24 hours apart
Replacement flluid- 5% human albumin
Monitor VS every 15 min
Measure PT,PTT and pre&post procedure RP, LFT, FBC
Anticoagulation: Heparin 50u/kg stat than 1000u/h
target ACT 1.5-2.0X normal
adjust dose accordingly
stop heparin 30min prior to end of procedure
To avoid hemolysis, PE must be done at
TMP 50-60mmHg
Qb 100-150mls/min
Complications of PE
Hypotension- bld loss, decrease oncotic pressure
Bleeding d/t reduction in coagulation factors
Edema- reduction of intravascular oncotic pressure
Loss of cellular elements
Ethylene Oxide hypersensitivity
Related to anticoagulation
Bleeding- heparin related
Hypocalcemia leading to arrhythmias/ hypotension/ numbness/ tingling sensation
PV= (1-Hct)(b+cW)
Hct= Hematocrit
b=1530 for males, 864 for females
c=41 for males, 47.2 for females
W= lean body weight
Rough estimation: at Hct 45.
Plasma Volume=40ml/kg (BW)
Usually 5-7 sessions of plasmapheresis is required exchanges is usu done 24 hours apart
Replacement flluid- 5% human albumin
Monitor VS every 15 min
Measure PT,PTT and pre&post procedure RP, LFT, FBC
Anticoagulation: Heparin 50u/kg stat than 1000u/h
target ACT 1.5-2.0X normal
adjust dose accordingly
stop heparin 30min prior to end of procedure
To avoid hemolysis, PE must be done at
TMP 50-60mmHg
Qb 100-150mls/min
Complications of PE
Hypotension- bld loss, decrease oncotic pressure
Bleeding d/t reduction in coagulation factors
Edema- reduction of intravascular oncotic pressure
Loss of cellular elements
Ethylene Oxide hypersensitivity
Related to anticoagulation
Bleeding- heparin related
Hypocalcemia leading to arrhythmias/ hypotension/ numbness/ tingling sensation
Thursday, November 27, 2008
Thalidomide
WARNING
SEVERE, LIFE-THREATENING HUMAN BIRTH DEFECTS.
IF THALIDOMIDE IS TAKEN DURING PREGNANCY, IT CAN CAUSE SEVERE BIRTH DEFECTS OR DEATH TO AN UNBORN BABY. THALIDOMIDE SHOULD NEVER BE USED BY WOMEN WHO ARE PREGNANT OR WHO COULD BECOME PREGNANT WHILE TAKING THE DRUG. EVEN A SINGLE DOSE [1 CAPSULE (REGARDLESS OF STRENGTH)] TAKEN BY A PREGNANT WOMAN DURING HER PREGNANCY CAN CAUSE SEVERE BIRTH DEFECTS.
BECAUSE OF THIS TOXICITY AND IN AN EFFORT TO MAKE THE CHANCE OF FETAL EXPOSURE TO THALOMID® (thalidomide) AS NEGLIGIBLE AS POSSIBLE, THALOMID® (thalidomide) IS APPROVED FOR MARKETING ONLY UNDER A SPECIAL RESTRICTED DISTRIBUTION PROGRAM APPROVED BY THE FOOD AND DRUG ADMINISTRATION. THIS PROGRAM IS CALLED THE "SYSTEM FOR THALIDOMIDE EDUCATION AND PRESCRIBING SAFETY (S.T.E.P.S.® )".
UNDER THIS RESTRICTED DISTRIBUTION PROGRAM, ONLY PRESCRIBERS AND PHARMACISTS REGISTERED WITH THE PROGRAM ARE ALLOWED TO PRESCRIBE AND DISPENSE THE PRODUCT. IN ADDITION, PATIENTS MUST BE ADVISED OF, AGREE TO, AND COMPLY WITH THE REQUIREMENTS OF THE S.T.E.P.S.® PROGRAM IN ORDER TO RECEIVE PRODUCT.
PLEASE SEE THE FOLLOWING BOXED WARNINGS CONTAINING SPECIAL INFORMATION FOR PRESCRIBERS, FEMALE PATIENTS, AND MALE PATIENTS ABOUT THIS RESTRICTED DISTRIBUTION PROGRAM.
PRESCRIBERS
THALOMID® (thalidomide) may be prescribed only by licensed prescribers who are registered in the S.T.E.P.S.® program and understand the risk of teratogenicity if thalidomide is used during pregnancy.
Major human fetal abnormalities related to thalidomide administration during pregnancy have been documented: amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micro pinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented.1 Mortality at or shortly after birth has been reported at about 40%.2
Effective contraception (see CONTRAINDICATIONS) must be used for at least 4 weeks before beginning thalidomide therapy, during thalidomide therapy, and for 4 weeks following discontinuation of thalidomide therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or because the patient has been postmenopausal for at least 24 months. Two reliable forms of contraception must be used simultaneously unless continuous abstinence from heterosexual sexual contact is the chosen method. Women of childbearing potential should be referred to a qualified provider of contraceptive methods, if needed. Sexually mature women who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be women of childbearing potential.
Before starting treatment, women of childbearing potential should have a pregnancy test (sensitivity of at least 50 mIU/mL). The test should be performed within the 24 hours prior to beginning thalidomide therapy. A prescription for thalidomide for a woman of childbearing potential must not be issued by the prescriber until a written report of a negative pregnancy test has been obtained by the prescriber.
Male Patients: Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex condom during any sexual contact with women of childbearing potential even if he has undergone a successful vasectomy.
Once treatment has started, pregnancy testing should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated at 4 weeks in women with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in menstrual bleeding.
If pregnancy does occur during thalidomide treatment, thalidomide must be discontinued immediately.
Any suspected fetal exposure to THALOMID® (thalidomide) must be reported immediately to the FDA via the MedWatch number at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436. The patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.
FEMALE PATIENTS
Thalidomide is contraindicated in WOMEN of childbearing potential unless alternative therapies are considered inappropriate AND the patient MEETS ALL OF THE FOLLOWING CONDITIONS (i.e., she is essentially unable to become pregnant while on thalidomide therapy):
* she understands and can reliably carry out instructions.
* she is capable of complying with the mandatory contraceptive measures, pregnancy testing, patient registration, and patient survey as described in the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.® ) program.
* she has received both oral and written warnings of the hazards of taking thalidomide during pregnancy and of exposing a fetus to the drug.
* she has received both oral and written warnings of the risk of possible contraception failure and of the need to use two reliable forms of contraception simultaneously (see CONTRAINDICATIONS), unless continuous abstinence from heterosexual sexual contact is the chosen method. Sexually mature women who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be women of childbearing potential.
* she acknowledges, in writing, her understanding of these warnings and of the need for using two reliable methods of contraception for 4 weeks prior to beginning thalidomide therapy, during thalidomide therapy, and for 4 weeks after discontinuation of thalidomide therapy.
* she has had a negative pregnancy test with a sensitivity of at least 50 mIU/mL, within the 24 hours prior to beginning therapy. (See PRECAUTIONS, CONTRAINDICATIONS)
* if the patient is between 12 and 18 years of age, her parent or legal guardian must have read this material and agreed to ensure compliance with the above.
MALE PATIENTS
Thalidomide is contraindicated in sexually mature MALES unless the PATIENT MEETS ALL OF THE FOLLOWING CONDITIONS:
* he understands and can reliably carry out instructions.
* he is capable of complying with the mandatory contraceptive measures that are appropriate for men, patient registration, and patient survey as described in the S.T.E.P.S.® program.
* he has received both oral and written warnings of the hazards of taking thalidomide and exposing a fetus to the drug.
* he has received both oral and written warnings of the risk of possible contraception failure and of the presence of thalidomide in semen. He has been instructed that he must always use a latex condom during any sexual contact with women of childbearing potential, even if he has undergone a successful vasectomy.
* he acknowledges, in writing, his understanding of these warnings and of the need to use a latex condom during any sexual contact with women of childbearing potential, even if he has undergone a successful vasectomy. Sexually mature women who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at any time in the preceding 24 consecutive months) are considered to be women of childbearing potential.
* if the patient is between 12 and 18 years of age, his parent or legal guardian must have read this material and agreed to ensure compliance with the above.
VENOUS THROMBOEMBOLIC EVENTS
The use of THALOMID® (thalidomide) in multiple myeloma results in an increased risk of venous thromboembolic events, such as deep venous thrombosis and pulmonary embolus. This risk increases significantly when thalidomide is used in combination with standard chemotherapeutic agents including dexamethasone. In one controlled trial, the rate of venous thromboembolic events was 22.5% in patients receiving thalidomide in combination with dexamethasone compared to 4.9% in patients receiving dexamethasone alone (p = 0.002). Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Preliminary data suggest that patients who are appropriate candidates may benefit from concurrent prophylactic anticoagulation or aspirin treatment.
DRUG DESCRIPTION
THALOMID® (thalidomide), α-(N-phthalimido) glutarimide, is an immunomodulatory agent. The empirical formula for thalidomide is C13H10N2O4 and the gram molecular weight is 258.2. The CAS number of thalidomide is 50-35-1.
Thalidomide is an off-white to white, odorless, crystalline powder that is soluble at 25°C in dimethyl sulfoxide and sparingly soluble in water and ethanol. The glutarimide moiety contains a single asymmetric center and, therefore, may exist in either of two optically active forms designated S-(-) or R-(+). THALOMID® (thalidomide) is an equal mixture of the S-(-) and R-(+) forms and, therefore, has a net optical rotation of zero.
THALOMID® (thalidomide) is available in 50 mg, 100 mg, 150 mg and 200 mg capsules for oral administration. Active ingredient: thalidomide. Inactive ingredients: pregelatinized starch and magnesium stearate. The 50 mg capsule shell contains gelatin, titanium dioxide, and black ink. The 100 mg capsule shell contains black iron oxide, yellow iron oxide, titanium dioxide, gelatin, and black ink. The 150 mg capsule shell contains FD&C blue #2, black iron oxide, yellow iron oxide, titanium dioxide, gelatin, and black and white ink. The 200 mg capsule shell contains FD&C blue #2, titanium dioxide, gelatin, and white ink.
Other common side effects
Thalidomide is associated with:-
drowsiness/somnolence,
peripheral neuropathy,
dizziness/orthostatic hypotension,
neutro-penia, and
HIV viral load increase.
Hypersensitivity to THALOMID® (thalidomide) and bradycardia in patients treated with thalidomide have been reported.
Somnolence, dizziness, and rash are the most commonly observed adverse events associated with the use of thalidomide.
SEVERE, LIFE-THREATENING HUMAN BIRTH DEFECTS.
IF THALIDOMIDE IS TAKEN DURING PREGNANCY, IT CAN CAUSE SEVERE BIRTH DEFECTS OR DEATH TO AN UNBORN BABY. THALIDOMIDE SHOULD NEVER BE USED BY WOMEN WHO ARE PREGNANT OR WHO COULD BECOME PREGNANT WHILE TAKING THE DRUG. EVEN A SINGLE DOSE [1 CAPSULE (REGARDLESS OF STRENGTH)] TAKEN BY A PREGNANT WOMAN DURING HER PREGNANCY CAN CAUSE SEVERE BIRTH DEFECTS.
BECAUSE OF THIS TOXICITY AND IN AN EFFORT TO MAKE THE CHANCE OF FETAL EXPOSURE TO THALOMID® (thalidomide) AS NEGLIGIBLE AS POSSIBLE, THALOMID® (thalidomide) IS APPROVED FOR MARKETING ONLY UNDER A SPECIAL RESTRICTED DISTRIBUTION PROGRAM APPROVED BY THE FOOD AND DRUG ADMINISTRATION. THIS PROGRAM IS CALLED THE "SYSTEM FOR THALIDOMIDE EDUCATION AND PRESCRIBING SAFETY (S.T.E.P.S.® )".
UNDER THIS RESTRICTED DISTRIBUTION PROGRAM, ONLY PRESCRIBERS AND PHARMACISTS REGISTERED WITH THE PROGRAM ARE ALLOWED TO PRESCRIBE AND DISPENSE THE PRODUCT. IN ADDITION, PATIENTS MUST BE ADVISED OF, AGREE TO, AND COMPLY WITH THE REQUIREMENTS OF THE S.T.E.P.S.® PROGRAM IN ORDER TO RECEIVE PRODUCT.
PLEASE SEE THE FOLLOWING BOXED WARNINGS CONTAINING SPECIAL INFORMATION FOR PRESCRIBERS, FEMALE PATIENTS, AND MALE PATIENTS ABOUT THIS RESTRICTED DISTRIBUTION PROGRAM.
PRESCRIBERS
THALOMID® (thalidomide) may be prescribed only by licensed prescribers who are registered in the S.T.E.P.S.® program and understand the risk of teratogenicity if thalidomide is used during pregnancy.
Major human fetal abnormalities related to thalidomide administration during pregnancy have been documented: amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micro pinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented.1 Mortality at or shortly after birth has been reported at about 40%.2
Effective contraception (see CONTRAINDICATIONS) must be used for at least 4 weeks before beginning thalidomide therapy, during thalidomide therapy, and for 4 weeks following discontinuation of thalidomide therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or because the patient has been postmenopausal for at least 24 months. Two reliable forms of contraception must be used simultaneously unless continuous abstinence from heterosexual sexual contact is the chosen method. Women of childbearing potential should be referred to a qualified provider of contraceptive methods, if needed. Sexually mature women who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be women of childbearing potential.
Before starting treatment, women of childbearing potential should have a pregnancy test (sensitivity of at least 50 mIU/mL). The test should be performed within the 24 hours prior to beginning thalidomide therapy. A prescription for thalidomide for a woman of childbearing potential must not be issued by the prescriber until a written report of a negative pregnancy test has been obtained by the prescriber.
Male Patients: Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex condom during any sexual contact with women of childbearing potential even if he has undergone a successful vasectomy.
Once treatment has started, pregnancy testing should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated at 4 weeks in women with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in menstrual bleeding.
If pregnancy does occur during thalidomide treatment, thalidomide must be discontinued immediately.
Any suspected fetal exposure to THALOMID® (thalidomide) must be reported immediately to the FDA via the MedWatch number at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436. The patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.
FEMALE PATIENTS
Thalidomide is contraindicated in WOMEN of childbearing potential unless alternative therapies are considered inappropriate AND the patient MEETS ALL OF THE FOLLOWING CONDITIONS (i.e., she is essentially unable to become pregnant while on thalidomide therapy):
* she understands and can reliably carry out instructions.
* she is capable of complying with the mandatory contraceptive measures, pregnancy testing, patient registration, and patient survey as described in the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.® ) program.
* she has received both oral and written warnings of the hazards of taking thalidomide during pregnancy and of exposing a fetus to the drug.
* she has received both oral and written warnings of the risk of possible contraception failure and of the need to use two reliable forms of contraception simultaneously (see CONTRAINDICATIONS), unless continuous abstinence from heterosexual sexual contact is the chosen method. Sexually mature women who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be women of childbearing potential.
* she acknowledges, in writing, her understanding of these warnings and of the need for using two reliable methods of contraception for 4 weeks prior to beginning thalidomide therapy, during thalidomide therapy, and for 4 weeks after discontinuation of thalidomide therapy.
* she has had a negative pregnancy test with a sensitivity of at least 50 mIU/mL, within the 24 hours prior to beginning therapy. (See PRECAUTIONS, CONTRAINDICATIONS)
* if the patient is between 12 and 18 years of age, her parent or legal guardian must have read this material and agreed to ensure compliance with the above.
MALE PATIENTS
Thalidomide is contraindicated in sexually mature MALES unless the PATIENT MEETS ALL OF THE FOLLOWING CONDITIONS:
* he understands and can reliably carry out instructions.
* he is capable of complying with the mandatory contraceptive measures that are appropriate for men, patient registration, and patient survey as described in the S.T.E.P.S.® program.
* he has received both oral and written warnings of the hazards of taking thalidomide and exposing a fetus to the drug.
* he has received both oral and written warnings of the risk of possible contraception failure and of the presence of thalidomide in semen. He has been instructed that he must always use a latex condom during any sexual contact with women of childbearing potential, even if he has undergone a successful vasectomy.
* he acknowledges, in writing, his understanding of these warnings and of the need to use a latex condom during any sexual contact with women of childbearing potential, even if he has undergone a successful vasectomy. Sexually mature women who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at any time in the preceding 24 consecutive months) are considered to be women of childbearing potential.
* if the patient is between 12 and 18 years of age, his parent or legal guardian must have read this material and agreed to ensure compliance with the above.
VENOUS THROMBOEMBOLIC EVENTS
The use of THALOMID® (thalidomide) in multiple myeloma results in an increased risk of venous thromboembolic events, such as deep venous thrombosis and pulmonary embolus. This risk increases significantly when thalidomide is used in combination with standard chemotherapeutic agents including dexamethasone. In one controlled trial, the rate of venous thromboembolic events was 22.5% in patients receiving thalidomide in combination with dexamethasone compared to 4.9% in patients receiving dexamethasone alone (p = 0.002). Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Preliminary data suggest that patients who are appropriate candidates may benefit from concurrent prophylactic anticoagulation or aspirin treatment.
DRUG DESCRIPTION
THALOMID® (thalidomide), α-(N-phthalimido) glutarimide, is an immunomodulatory agent. The empirical formula for thalidomide is C13H10N2O4 and the gram molecular weight is 258.2. The CAS number of thalidomide is 50-35-1.
Thalidomide is an off-white to white, odorless, crystalline powder that is soluble at 25°C in dimethyl sulfoxide and sparingly soluble in water and ethanol. The glutarimide moiety contains a single asymmetric center and, therefore, may exist in either of two optically active forms designated S-(-) or R-(+). THALOMID® (thalidomide) is an equal mixture of the S-(-) and R-(+) forms and, therefore, has a net optical rotation of zero.
THALOMID® (thalidomide) is available in 50 mg, 100 mg, 150 mg and 200 mg capsules for oral administration. Active ingredient: thalidomide. Inactive ingredients: pregelatinized starch and magnesium stearate. The 50 mg capsule shell contains gelatin, titanium dioxide, and black ink. The 100 mg capsule shell contains black iron oxide, yellow iron oxide, titanium dioxide, gelatin, and black ink. The 150 mg capsule shell contains FD&C blue #2, black iron oxide, yellow iron oxide, titanium dioxide, gelatin, and black and white ink. The 200 mg capsule shell contains FD&C blue #2, titanium dioxide, gelatin, and white ink.
Other common side effects
Thalidomide is associated with:-
drowsiness/somnolence,
peripheral neuropathy,
dizziness/orthostatic hypotension,
neutro-penia, and
HIV viral load increase.
Hypersensitivity to THALOMID® (thalidomide) and bradycardia in patients treated with thalidomide have been reported.
Somnolence, dizziness, and rash are the most commonly observed adverse events associated with the use of thalidomide.
Plasmapheresis Protocol- Addenbrooke's Hospital
Dose:-
7 sessions over 14 days
60mls/kg
5% Albumin
Use of FFP at end of procedure- at discretion of treating doctor
Other aspects of plasma-exchange applies.
Anticoagulation: Heparin 50u/kg stat than 1000u/h
target ACT 1.5-2.0X normal
adjust dose accordingly
stop heparin 30min prior to end of procedure
To avoid hemolysis, PEx must be done at
TMP 50-60mmHg
Qb 100-150mls/min
Complications of PEx
Hypotension- bld loss, decrease oncotic pressure
Bleeding d/t reduction in coagulation factors
Edema- reduction of intravascular oncotic pressure
Loss of cellular elements
Ethylene Oxide hypersensitivity
Related to anticoagulation
Bleeding- heparin related
Hypocalcemia leading to arrhythmias/ hypotension/ numbness/ tingling sensation
7 sessions over 14 days
60mls/kg
5% Albumin
Use of FFP at end of procedure- at discretion of treating doctor
Other aspects of plasma-exchange applies.
Anticoagulation: Heparin 50u/kg stat than 1000u/h
target ACT 1.5-2.0X normal
adjust dose accordingly
stop heparin 30min prior to end of procedure
To avoid hemolysis, PEx must be done at
TMP 50-60mmHg
Qb 100-150mls/min
Complications of PEx
Hypotension- bld loss, decrease oncotic pressure
Bleeding d/t reduction in coagulation factors
Edema- reduction of intravascular oncotic pressure
Loss of cellular elements
Ethylene Oxide hypersensitivity
Related to anticoagulation
Bleeding- heparin related
Hypocalcemia leading to arrhythmias/ hypotension/ numbness/ tingling sensation
Azathioprine
After hepatic conversion to 6-mercaptopurine, the cytotoxic effects of azathioprine are mediated by the impairment of purine synthesis, incorporation of purines into DNA, and impairment of the endonuclease repair activity of DNA polymerase (20). The drug is well-absorbed after oral administration and elimination requires hepatic metabolism by xanthine oxidase; an important drug interaction is with xanthine oxidase inhibitors, such as allopurinol. Lymphocyte function is reduced, B-cells more than T-cells, and there is suppression of the cellular component of the inflammatory response. The major adverse effects are nausea and vomiting, dose-dependent myelosuppression and reversible, cholestatic, hepatic toxicity. An increased incidence of malignancies, particularly lymphomas and skin cancers, has been observed with prolonged administration after organ transplantation
Cyclophosphamide
Cyclophosphamide is an inactive pro-drug, converted by the mixed function oxidase system in the liver to the alkylating agents 4-hydroxy-cyclophosphamide and phosphoramide mustard, which alkylate guanine nucleotides, thus blocking cell division (20). Bioavailability after oral administration is greater than 75%, but there are large variations between individuals in the rate of production of active metabolites. A phenotypic variation in carboxylator activity affects the production of the inactive metabolite carboxyphosphoramide from 4-hydroxy-cyclophosphamide, which may influence efficacy and toxicity. The relation of renal and hepatic failure to the production and elimination of active metabolites has not been fully determined. Bladder toxicity is caused by renal excretion of the metabolite acrolein which can cause haemorrhagic cystitis and a markedly increased risk of bladder cancer (20). Other adverse effects include nausea and vomiting, myelosuppression with neutropenia, infections due to immunosuppression (4), alopecia and infertility. Permanent ovarian failure occurs in over 50% of women after one year’s exposure and is age-related; male infertility has been less well studied. The incidence of leukaemia and /or lymphoma is increased tenfold; less common adverse effects include pulmonary fibrosis, hepatitis and the syndrome of inappropriate ADH secretion.
RITUXIMAB
Administration
* DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS
* Premedicate before each infusion.
Administer only as an intravenous infusion
* Interrupt the infusion or slow the infusion rate for infusion reactions (see BOXED WARNING and WARNINGS AND PRECAUTIONS)
* First infusion: Initiate infusion at a rate of 50 mg/hr. In the absence of infusion toxicity, increase infusion rate by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr
* Subsequent infusions: Initiate infusion at a rate of 100 mg/hr. In the absence of infusion toxicity, increase rate by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr
Preparation
* RITUXAN is supplied as 100 mg/10 mL (NDC 50242-051-21) and 500 mg/50 mL (NDC 50242-053-06) solution in a single-use vial
Stability and storage
* RITUXAN vials are stable at 2°C–8°C (36°F–46°F). Do not use beyond expiration date stamped on carton. RITUXAN vials should be protected from direct sunlight. Do not freeze or shake
* RITUXAN solutions for infusion may be stored at 2°C–8°C (36°F–46°F) for 24 hours. RITUXAN solutions for infusion have been shown to be stable for an additional 24 hours at room temperature. However, since RITUXAN solutions do not contain a preservative, diluted solutions should be stored refrigerated (2°C–8°C). No incompatibilities between RITUXAN and polyvinylchloride or polyethylene bags have been observed.
WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
Infusion Reactions
Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue Rituxan infusion and provide medical treatment for Grade 3 or 4 infusion reactions.
Tumor Lysis Syndrome (TLS)
Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin's lymphoma (NHL) patients with Rituxan.
Severe Mucocutaneous Reactions
Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan.
Progressive Multifocal Leukoencephalopathy (PML)
JC virus infection resulting in PML and death can occur in patients receiving Rituxan.
Premedication:-
We give the following:-
PO Paracetamol 1g
IV Chlorpheniramine 10mg
+/- IV Methylprednisolone
We have used the following Rituximab dosing protocol for our vasculitis patients in Addenbrooke's Hospital, Cambridge.
Rituximab 1g X 2 doses 2 weeks apart
Then 1g 6 monthly for 2 years.
* DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS
* Premedicate before each infusion.
Administer only as an intravenous infusion
* Interrupt the infusion or slow the infusion rate for infusion reactions (see BOXED WARNING and WARNINGS AND PRECAUTIONS)
* First infusion: Initiate infusion at a rate of 50 mg/hr. In the absence of infusion toxicity, increase infusion rate by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr
* Subsequent infusions: Initiate infusion at a rate of 100 mg/hr. In the absence of infusion toxicity, increase rate by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr
Preparation
* RITUXAN is supplied as 100 mg/10 mL (NDC 50242-051-21) and 500 mg/50 mL (NDC 50242-053-06) solution in a single-use vial
Stability and storage
* RITUXAN vials are stable at 2°C–8°C (36°F–46°F). Do not use beyond expiration date stamped on carton. RITUXAN vials should be protected from direct sunlight. Do not freeze or shake
* RITUXAN solutions for infusion may be stored at 2°C–8°C (36°F–46°F) for 24 hours. RITUXAN solutions for infusion have been shown to be stable for an additional 24 hours at room temperature. However, since RITUXAN solutions do not contain a preservative, diluted solutions should be stored refrigerated (2°C–8°C). No incompatibilities between RITUXAN and polyvinylchloride or polyethylene bags have been observed.
WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
Infusion Reactions
Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue Rituxan infusion and provide medical treatment for Grade 3 or 4 infusion reactions.
Tumor Lysis Syndrome (TLS)
Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin's lymphoma (NHL) patients with Rituxan.
Severe Mucocutaneous Reactions
Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan.
Progressive Multifocal Leukoencephalopathy (PML)
JC virus infection resulting in PML and death can occur in patients receiving Rituxan.
Premedication:-
We give the following:-
PO Paracetamol 1g
IV Chlorpheniramine 10mg
+/- IV Methylprednisolone
We have used the following Rituximab dosing protocol for our vasculitis patients in Addenbrooke's Hospital, Cambridge.
Rituximab 1g X 2 doses 2 weeks apart
Then 1g 6 monthly for 2 years.
RITUXVAS
Background
1.1.The diseases
Wegener's granulomatosis (WG) and microscopic polyangiitis (MP) are syndromes of primary systemic vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA) (appendix 1)(15,16,19). WG and MP share many histological features, including a necrotising glomerulonephritis which often leads to rapidly progressive renal failure. Isolated pauci-immune necrotising, cresentic glomerulonephritis, has many features to suggest that it represents a renal-limited form of vasculitis (RLV), including the presence of circulating anti-MPO or anti-Pr3 antibodies. Common histological and serological features, and a similar response to treatment, have justified a common approach to the treatment of WG, MP and RLV. These diseases are sub grouped according to severity. ‘Generalised’ vasculitis refers to systemic disease with renal involvement (creatinine up to 500) and or other imminent vital organ failure. Patients with ‘generalised’ vasculitis and those with more severe renal vasculitis (i.e. creatinine greater than 500) will be included in this trial.
1.2.Their treatment
Untreated generalised WG and MP follow a progressive course with fatal outcome due to vital organ failure (17). With the empirical introduction of corticosteroids and cytotoxic agents, five year survival has increased from under 20% to over 60% (18). Over the last decade the treatment of AASV has been standardised following the results of randomised trials. Cyclophosphamide (either daily oral or intravenous (IV) pulse) and prednisolone are used for remission induction (3 to 6 months) with longer therapy of azathioprine or methotrexate and low dose steroids to prevent disease relapse. Early systemic vasculitis may be treated with methotrexate in place of cyclophosphamide. The addition of plasma exchange improves renal recovery rates in severe renal vasculitis. Adverse events with current therapy are frequent and are the major cause of mortality. The frequency of severe adverse events (10-45%) is influenced by age and the severity of renal involvement. There is a clear need for a new safer, effective therapy for AASV (1,2,3,6). In order to address the questions of drug toxicity and frequent disease relapses, newer therapies with better safety profiles have been investigated in AASV. One such agent is rituximab, a murine/human chimeric anti CD 20 monoclonal antibody. Its use results in B cell depletion for 6-18 months (7). B cells are key factors in autoimmune diseases with roles in autoantibody production, cytokine release and antigen presentation to T-cells. The sequence of immune events that trigger AASV are not fully understood, however evidence suggests that ANCA are pathogenic (21). Thus interruption of the cell line leading to ANCA production may be beneficial in disease suppression. Rituximab is an established treatment in non-Hodgkin’s lymphoma with a good safety track record (7). Even though the individual is rendered B cell deplete, immunoglobulin levels are maintained, and infection rates are low. Recently its use in autoimmune diseases has been realised with excellent results in rheumatoid arthritis (8). Rituximab has been shown to be effective in AASV, inducing remission in patients intolerant of cyclophosphamide (5,10-12,22,26-28). Given its good safety profile and efficacy its use a first line agent in AASV needs to be investigated.
In RITUXVAS, a rituximab based regimen will be compared with a standard cyclophosphamide/azathioprine based regimen in the treatment of AASV with glomerulonephritis. In order to achieve results applicable to clinical practice, all cases from mild to severe renal failure will be included. Standard practice includes the use of oral steroids which will be applied similarly in both treatment groups. It is recognised that necrotising cresentic glomerulonephritis progresses rapidly and immediate immune suppression is required to reverse existing and spare further organ damage. The therapeutic effect of rituximab is not immediate. Therefore two initial doses of cyclophosphamide will be given along side rituximab, thus allowing early disease control. When dialysis dependant renal failure or pulmonary haemorrhage occur, plasma exchange or intravenous steroids are standard additional therapies. These will be allowed according to local practice, and randomisation will occur after plasma exchange. Patients in the cyclophosphamide limb will receive azathioprine as remission maintenance therapy. Patients receiving rituximab will not receive any additional maintenance therapy.
1.3. Rituximab
Rituximab is an anti CD 20 chimeric mouse/human monoclonal antibody, with human IgG1 constant regions and murine light/heavy chain variable regions (7). CD 20 is a ligand which exists on developing B cells, excluding stem cells and plasma cells. The role of the CD 20 ligand in nature is not fully understood, although mediation of apoptosis has been suggested. The mechanisms by which rituximab causes B cell depletion may involve complement induced B cell lysis, Fc receptor mediated cytotoxic cell killing or the direct induction of B cell apoptosis by rituximab. Rituximab therapy correlates positively with B cell depletion and rituximab levels. Different dosing regimens have been trialled. In patients with systemic lupus erythematosus (SLE), the efficacy of rituximab is dependant upon B cell depletion. 4 infusions of 375mg/m2 rituximab infusions (one per week for four weeks) were required for this to occur (13,14). In 3 published reports 375mg/m2 has resulted in B cell depletion and clinical response in patients with refractory vasculitis (10-13). On the basis of these results a dose of 4 x 375mg/m2 infusions will be used in RITUXVAS. In RITUXVAS, 2 doses cyclophosphamide will still be administered with the 1st and 3rd rituximab infusions, for two reasons. Firstly, the necrotising cresentic glomerulonephritis associated with AASV progresses rapidly and the therapeutic effect of rituximab is delayed. The use of cyclophosphamide/high dose steroid, which are standard components of induction therapy, will allow adequate immunosuppression in the early crucial treatment of AASV. Secondly, human antichimeric antibody (HACA) formation has been reported in NHL, SLE, and RA with varying frequencies, (4.3% of patients in RA (8)). The long term implications of these antibodies are not known. However, the possibility of anaphylactic reactions and rituximab resistance with further treatments exists. Co-administration of an immunosuppressant effective in the treatment of vasculitis is thus a logical approach to minimise HACA development. Rituximab has now been used to treat 300,000 patients with NHL. Long-term safety regarding carcinogenicity and fertility has yet to be established. However, no major long-term adverse sequelae have been reported (1). Up to 50% of patients receiving rituximab for an indication will develop infusion reactions with symptoms including; fevers, chills, rigors, flushing, throat irritation RITUXVAS EUVAS Trial 9
EUDRACT 2005-003610-15 rash rhinitis fatigue headache, nausea, vomiting, urticaria, angioedema, bronchospasm, myalgia, arthralgia, hypotension, hypertension and exacerbation of angina or congestive cardiac failure. Later reactions include diarrhoea, leucopenia, neutropenia, thrombocytopenia, anaemia, and infections in 30%, which may or may not be drug related (investigators brochure).
1.4. Aims of RITUXVAS:
1 To assess the rates of preliminary response and sustained remission of AASV following rituximab (on the basis of former studies, 86% sustained remission expected with rituximab compared to 75% in control group). 2 To assess safety of a rituximab regimen in terms of severe adverse events (in patients receiving standard therapies, adverse advent rate is 45% at 2 years, at least 50% of which are infection relapted. In comparison rituximab use is only rarely associated with infections, therefore 22.5% adverse event rate expected with rituximab compared to 45% at 2 years in control group).
2. Hypothesis: Rituximab leads to a higher rate of sustained remission compared to standard therapies (cyclophosphamide/azathioprine) with a lower rate of severe adverse events and reduced cyclophosphamide exposure.
3. Trial Design
International, randomised, controlled, prospective, open trial comparing a rituximab based regimen with a standard cyclophosphamide/azathioprine regimen in the treatment of active ‘generalised’ AASV. Informed consent and ethics committee approval will be obtained.
3.1. Inclusion Criteria (all four must be present)
1. A new diagnosis of WG, MP or renal-limited vasculitis (RLV)(appendix 1) 2. Renal involvement attributable to active WG, MP or RLV with at least one of the following: a) Biopsy demonstrating necrotizing glomerulonephritis. b) Red cell casts on urine microscopy or ≥ ++ haematuria 3. ANCA positivity ANCA positivity requires either (a) or (b) (a) PR3-ANCA by ELISA or a typical cANCA pattern by indirect immunofluorescence (IIF), or both. (b) MPO-ANCA by ELISA. A positive pANCA by IIF requires confirmation by MPO-ANCA ELISA.
3.2. Exclusion Criteria
1. Previous cyclophosphamide, (greater than 2 weeks of an oral or IV pulse cyclophosphamide regimen). 2. Co-existence of another multisystem autoimmune disease, e.g. SLE, Churg Strauss Syndrome, Henoch Schonlein Purpura, rheumatoid vasculitis, essential mixed cryoglobulinaemia, anti-glomerular basement membrane antibody positivity 3. Hepatitis B e antigen positive or Hepatitis C antibody positive. 4. Known HIV positive (HIV testing will not be a requirement for this trial). 5. Previous malignancy (usually exclude unless agreed with trial co-ordinator). 6. Pregnancy, breast feeding or inadequate contraception if female. 7 Allergy to a study medication 8 Live Vaccine within last 4 weeks
3.3. Randomisation
1 Variables known to influence primary end points will be balanced between groups by minimisation i Age ii Disease WG or MP/RLV iii Creatinine 2 Randomisation form (see TMF) sent by e-mail rbjones@doctors.org.uk or fax to 01223 586506 (clinical trials office).
3.4. Endpoints Primary end points will be assessed upon trial completion at 2 years. However interim analyses will be performed when 1 30 patients have completed 6 weeks, to assess efficacy (treatment response) and safety (severe adverse events). 2 40 patients have completed 6 months to assess efficacy (remission rates) and safety (severe adverse events).
i Primary
1 Sustained remission (BVAS = 0 at 6 months and sustained for 6 months). 2 Severe adverse events (CTCAE grade ≥ 3) at 2 years.
ii Secondary 1 Efficacy
Response rate at 6 weeks (BVAS < 50% baseline) Remission at 6 months (BVAS=0 for 2 months by 6 months) Time to remission (BVAS=0) Relapses (all relapses and major/minor) BVAS area under the curve Change in GFR Change in SF-36 Change in VDI
2. Safety Severe adverse events (CTCAE grade ≥ 3) at 6 weeks and 6 months
All adverse events Death Prednisolone cumulative dose Cyclophosphamide cumulative dose
iii Tertiary
Human anti-chimeric antibody testing Correlation of B cells with disease activity Change in ANCA and disease activity Histopathology predictors of outcome
3.5. Interventions
I Drug regimens a) Rituximab Regimen: Rituximab, 375mg/m2 IV once a week for 4 weeks (i.e. 4 doses total), with 2 doses of cyclophosphamide 15mg/kg, 2 weeks apart given with the 1st and 3rd rituximab dose (appendix 3).
b) Control (cyclophosphamide/azathioprine) Regimen; Cyclophosphamide 15mg/kg for 3-6 months (6-10 doses total) to be given IV according to protocol (appendix 3) for remission induction. Cyclophosphamide should be converted to azathioprine for remission maintenance. c) Steroids. All patients will receive 1g IV methylprednisolone, then same daily oral corticosteroid regimen (appendix 3). d) Plasma exchange or IV methylprednisolone will be allowed according to local practice for patients with organ threatening disease. NB randomisation should not occur until completion of plasma exchange to avoid loss of rituximab during plasma exchange. The first dose of cyclophosphamide can be given prior to completion of plasma exchange. e) Progressive disease Within the first 6 months disease progression defined as a persistence of nephritic sediment or activity on a renal biopsy and a failure to improve GFR≥ 10 mls/min, if GFR at diagnosis is < 50 mls/min (calculated by cockcroft gault formula, see TMF for formula) OR persistence or new occurrence of a major non-renal BVAS item at 6 weeks then additional treatment should occur: i) Rituximab limb: 3rd dose of cyclophosphamide (15mg/kg) ii) Cyclophosphamide limb: Plasma exchange or IV methylprednisolone (according to local practice). f) Relapse Therapy. Relapses will be categorised as major or minor.
i) Rituximab limb: Rituximab with steroid will be used for major and minor relapse. Additional cyclophosphamide may also be used for major relapse.
ii) Control limb: Increased azathioprine and steroid for minor relapse and cyclophosphamide and steroid for major relapse.
II Evaluations Study assessments (including history and examination) will be performed at entry, 1.5, 3, 6, 9, 12, 15, 18, 21 and 24 months and at the time of relapse (see appendix 5, and TMF for assessment schedule). At each assessment the following should be performed: a) Blood for routine testing. b) 10 mls serum saved for centralised immunological analysis (including ANCA) and HACA. c) BVAS for each assessment and at relapse;
Every 6 months SF-36 and VDI should be performed (23-25)(see TMF).
Initial Renal histology will be reviewed by a EUVAS panel of histopathologists, based in Milan.
3.6. Withdrawal and treatment failure
1 At patient's or physician's request. Reason for withdrawal is to be recorded in the CRF. 2 Patients not achieving remission within 6 months to be withdrawn from trial drug regimen and will be treated according to local practice. They will remain under trial follow up.
3.7. Adverse events
1 Adverse effects will be actively sought and recorded in CRFs at each evaluation (see section 4.5 and TMF). 2 Unexpected, severe adverse events attributable to study medication must be reported within 24 hours to trial management committee. (see TMF and section 4.5 for full details).
3.8. Statistical analysis
Primary end points will be assessed upon trial completion at 2 years. However interim analyses will be performed: (a) When 30 patients have completed 6 weeks trial participation to assess (1) treatment response (BVAS fall of > 50% baseline). (2) safety (adverse events CTCAE grade 3 or greater) and (b) When 40 patients have completed 6 months trial participation to assess (1) remission (BVAS 0 for 2 months by 6 months) (2) safety (adverse events CTCAE grade 3 or greater)Primary end point confidence Intervals. A total of 30 patients will receive rituximab. The expected sustained remission rate for rituximab is 86%, based on the results of former studies. The 95% confidence interval for a sustained remission rate of 86% is 70.3%-94.7% when the sample size is 30. The expected response rate of 86% is considered clinically significant as patients with active newly diagnosed generalised AASV without 3-6 months of cyclophosphamide are conventionally expected to experience disease progression (worsening of clinical signs and symptoms). The expected sustained remission rate in the control group is 75%. Analyses on the 40 patients should be considered exploratory.
3.9. Duration: 3 years: 6 months recruitment, two year follow-up per patient and 6 month analyses.
Visit the EUVAS website for details.
1.1.The diseases
Wegener's granulomatosis (WG) and microscopic polyangiitis (MP) are syndromes of primary systemic vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA) (appendix 1)(15,16,19). WG and MP share many histological features, including a necrotising glomerulonephritis which often leads to rapidly progressive renal failure. Isolated pauci-immune necrotising, cresentic glomerulonephritis, has many features to suggest that it represents a renal-limited form of vasculitis (RLV), including the presence of circulating anti-MPO or anti-Pr3 antibodies. Common histological and serological features, and a similar response to treatment, have justified a common approach to the treatment of WG, MP and RLV. These diseases are sub grouped according to severity. ‘Generalised’ vasculitis refers to systemic disease with renal involvement (creatinine up to 500) and or other imminent vital organ failure. Patients with ‘generalised’ vasculitis and those with more severe renal vasculitis (i.e. creatinine greater than 500) will be included in this trial.
1.2.Their treatment
Untreated generalised WG and MP follow a progressive course with fatal outcome due to vital organ failure (17). With the empirical introduction of corticosteroids and cytotoxic agents, five year survival has increased from under 20% to over 60% (18). Over the last decade the treatment of AASV has been standardised following the results of randomised trials. Cyclophosphamide (either daily oral or intravenous (IV) pulse) and prednisolone are used for remission induction (3 to 6 months) with longer therapy of azathioprine or methotrexate and low dose steroids to prevent disease relapse. Early systemic vasculitis may be treated with methotrexate in place of cyclophosphamide. The addition of plasma exchange improves renal recovery rates in severe renal vasculitis. Adverse events with current therapy are frequent and are the major cause of mortality. The frequency of severe adverse events (10-45%) is influenced by age and the severity of renal involvement. There is a clear need for a new safer, effective therapy for AASV (1,2,3,6). In order to address the questions of drug toxicity and frequent disease relapses, newer therapies with better safety profiles have been investigated in AASV. One such agent is rituximab, a murine/human chimeric anti CD 20 monoclonal antibody. Its use results in B cell depletion for 6-18 months (7). B cells are key factors in autoimmune diseases with roles in autoantibody production, cytokine release and antigen presentation to T-cells. The sequence of immune events that trigger AASV are not fully understood, however evidence suggests that ANCA are pathogenic (21). Thus interruption of the cell line leading to ANCA production may be beneficial in disease suppression. Rituximab is an established treatment in non-Hodgkin’s lymphoma with a good safety track record (7). Even though the individual is rendered B cell deplete, immunoglobulin levels are maintained, and infection rates are low. Recently its use in autoimmune diseases has been realised with excellent results in rheumatoid arthritis (8). Rituximab has been shown to be effective in AASV, inducing remission in patients intolerant of cyclophosphamide (5,10-12,22,26-28). Given its good safety profile and efficacy its use a first line agent in AASV needs to be investigated.
In RITUXVAS, a rituximab based regimen will be compared with a standard cyclophosphamide/azathioprine based regimen in the treatment of AASV with glomerulonephritis. In order to achieve results applicable to clinical practice, all cases from mild to severe renal failure will be included. Standard practice includes the use of oral steroids which will be applied similarly in both treatment groups. It is recognised that necrotising cresentic glomerulonephritis progresses rapidly and immediate immune suppression is required to reverse existing and spare further organ damage. The therapeutic effect of rituximab is not immediate. Therefore two initial doses of cyclophosphamide will be given along side rituximab, thus allowing early disease control. When dialysis dependant renal failure or pulmonary haemorrhage occur, plasma exchange or intravenous steroids are standard additional therapies. These will be allowed according to local practice, and randomisation will occur after plasma exchange. Patients in the cyclophosphamide limb will receive azathioprine as remission maintenance therapy. Patients receiving rituximab will not receive any additional maintenance therapy.
1.3. Rituximab
Rituximab is an anti CD 20 chimeric mouse/human monoclonal antibody, with human IgG1 constant regions and murine light/heavy chain variable regions (7). CD 20 is a ligand which exists on developing B cells, excluding stem cells and plasma cells. The role of the CD 20 ligand in nature is not fully understood, although mediation of apoptosis has been suggested. The mechanisms by which rituximab causes B cell depletion may involve complement induced B cell lysis, Fc receptor mediated cytotoxic cell killing or the direct induction of B cell apoptosis by rituximab. Rituximab therapy correlates positively with B cell depletion and rituximab levels. Different dosing regimens have been trialled. In patients with systemic lupus erythematosus (SLE), the efficacy of rituximab is dependant upon B cell depletion. 4 infusions of 375mg/m2 rituximab infusions (one per week for four weeks) were required for this to occur (13,14). In 3 published reports 375mg/m2 has resulted in B cell depletion and clinical response in patients with refractory vasculitis (10-13). On the basis of these results a dose of 4 x 375mg/m2 infusions will be used in RITUXVAS. In RITUXVAS, 2 doses cyclophosphamide will still be administered with the 1st and 3rd rituximab infusions, for two reasons. Firstly, the necrotising cresentic glomerulonephritis associated with AASV progresses rapidly and the therapeutic effect of rituximab is delayed. The use of cyclophosphamide/high dose steroid, which are standard components of induction therapy, will allow adequate immunosuppression in the early crucial treatment of AASV. Secondly, human antichimeric antibody (HACA) formation has been reported in NHL, SLE, and RA with varying frequencies, (4.3% of patients in RA (8)). The long term implications of these antibodies are not known. However, the possibility of anaphylactic reactions and rituximab resistance with further treatments exists. Co-administration of an immunosuppressant effective in the treatment of vasculitis is thus a logical approach to minimise HACA development. Rituximab has now been used to treat 300,000 patients with NHL. Long-term safety regarding carcinogenicity and fertility has yet to be established. However, no major long-term adverse sequelae have been reported (1). Up to 50% of patients receiving rituximab for an indication will develop infusion reactions with symptoms including; fevers, chills, rigors, flushing, throat irritation RITUXVAS EUVAS Trial 9
EUDRACT 2005-003610-15 rash rhinitis fatigue headache, nausea, vomiting, urticaria, angioedema, bronchospasm, myalgia, arthralgia, hypotension, hypertension and exacerbation of angina or congestive cardiac failure. Later reactions include diarrhoea, leucopenia, neutropenia, thrombocytopenia, anaemia, and infections in 30%, which may or may not be drug related (investigators brochure).
1.4. Aims of RITUXVAS:
1 To assess the rates of preliminary response and sustained remission of AASV following rituximab (on the basis of former studies, 86% sustained remission expected with rituximab compared to 75% in control group). 2 To assess safety of a rituximab regimen in terms of severe adverse events (in patients receiving standard therapies, adverse advent rate is 45% at 2 years, at least 50% of which are infection relapted. In comparison rituximab use is only rarely associated with infections, therefore 22.5% adverse event rate expected with rituximab compared to 45% at 2 years in control group).
2. Hypothesis: Rituximab leads to a higher rate of sustained remission compared to standard therapies (cyclophosphamide/azathioprine) with a lower rate of severe adverse events and reduced cyclophosphamide exposure.
3. Trial Design
International, randomised, controlled, prospective, open trial comparing a rituximab based regimen with a standard cyclophosphamide/azathioprine regimen in the treatment of active ‘generalised’ AASV. Informed consent and ethics committee approval will be obtained.
3.1. Inclusion Criteria (all four must be present)
1. A new diagnosis of WG, MP or renal-limited vasculitis (RLV)(appendix 1) 2. Renal involvement attributable to active WG, MP or RLV with at least one of the following: a) Biopsy demonstrating necrotizing glomerulonephritis. b) Red cell casts on urine microscopy or ≥ ++ haematuria 3. ANCA positivity ANCA positivity requires either (a) or (b) (a) PR3-ANCA by ELISA or a typical cANCA pattern by indirect immunofluorescence (IIF), or both. (b) MPO-ANCA by ELISA. A positive pANCA by IIF requires confirmation by MPO-ANCA ELISA.
3.2. Exclusion Criteria
1. Previous cyclophosphamide, (greater than 2 weeks of an oral or IV pulse cyclophosphamide regimen). 2. Co-existence of another multisystem autoimmune disease, e.g. SLE, Churg Strauss Syndrome, Henoch Schonlein Purpura, rheumatoid vasculitis, essential mixed cryoglobulinaemia, anti-glomerular basement membrane antibody positivity 3. Hepatitis B e antigen positive or Hepatitis C antibody positive. 4. Known HIV positive (HIV testing will not be a requirement for this trial). 5. Previous malignancy (usually exclude unless agreed with trial co-ordinator). 6. Pregnancy, breast feeding or inadequate contraception if female. 7 Allergy to a study medication 8 Live Vaccine within last 4 weeks
3.3. Randomisation
1 Variables known to influence primary end points will be balanced between groups by minimisation i Age ii Disease WG or MP/RLV iii Creatinine 2 Randomisation form (see TMF) sent by e-mail rbjones@doctors.org.uk or fax to 01223 586506 (clinical trials office).
3.4. Endpoints Primary end points will be assessed upon trial completion at 2 years. However interim analyses will be performed when 1 30 patients have completed 6 weeks, to assess efficacy (treatment response) and safety (severe adverse events). 2 40 patients have completed 6 months to assess efficacy (remission rates) and safety (severe adverse events).
i Primary
1 Sustained remission (BVAS = 0 at 6 months and sustained for 6 months). 2 Severe adverse events (CTCAE grade ≥ 3) at 2 years.
ii Secondary 1 Efficacy
Response rate at 6 weeks (BVAS < 50% baseline) Remission at 6 months (BVAS=0 for 2 months by 6 months) Time to remission (BVAS=0) Relapses (all relapses and major/minor) BVAS area under the curve Change in GFR Change in SF-36 Change in VDI
2. Safety Severe adverse events (CTCAE grade ≥ 3) at 6 weeks and 6 months
All adverse events Death Prednisolone cumulative dose Cyclophosphamide cumulative dose
iii Tertiary
Human anti-chimeric antibody testing Correlation of B cells with disease activity Change in ANCA and disease activity Histopathology predictors of outcome
3.5. Interventions
I Drug regimens a) Rituximab Regimen: Rituximab, 375mg/m2 IV once a week for 4 weeks (i.e. 4 doses total), with 2 doses of cyclophosphamide 15mg/kg, 2 weeks apart given with the 1st and 3rd rituximab dose (appendix 3).
b) Control (cyclophosphamide/azathioprine) Regimen; Cyclophosphamide 15mg/kg for 3-6 months (6-10 doses total) to be given IV according to protocol (appendix 3) for remission induction. Cyclophosphamide should be converted to azathioprine for remission maintenance. c) Steroids. All patients will receive 1g IV methylprednisolone, then same daily oral corticosteroid regimen (appendix 3). d) Plasma exchange or IV methylprednisolone will be allowed according to local practice for patients with organ threatening disease. NB randomisation should not occur until completion of plasma exchange to avoid loss of rituximab during plasma exchange. The first dose of cyclophosphamide can be given prior to completion of plasma exchange. e) Progressive disease Within the first 6 months disease progression defined as a persistence of nephritic sediment or activity on a renal biopsy and a failure to improve GFR≥ 10 mls/min, if GFR at diagnosis is < 50 mls/min (calculated by cockcroft gault formula, see TMF for formula) OR persistence or new occurrence of a major non-renal BVAS item at 6 weeks then additional treatment should occur: i) Rituximab limb: 3rd dose of cyclophosphamide (15mg/kg) ii) Cyclophosphamide limb: Plasma exchange or IV methylprednisolone (according to local practice). f) Relapse Therapy. Relapses will be categorised as major or minor.
i) Rituximab limb: Rituximab with steroid will be used for major and minor relapse. Additional cyclophosphamide may also be used for major relapse.
ii) Control limb: Increased azathioprine and steroid for minor relapse and cyclophosphamide and steroid for major relapse.
II Evaluations Study assessments (including history and examination) will be performed at entry, 1.5, 3, 6, 9, 12, 15, 18, 21 and 24 months and at the time of relapse (see appendix 5, and TMF for assessment schedule). At each assessment the following should be performed: a) Blood for routine testing. b) 10 mls serum saved for centralised immunological analysis (including ANCA) and HACA. c) BVAS for each assessment and at relapse;
Every 6 months SF-36 and VDI should be performed (23-25)(see TMF).
Initial Renal histology will be reviewed by a EUVAS panel of histopathologists, based in Milan.
3.6. Withdrawal and treatment failure
1 At patient's or physician's request. Reason for withdrawal is to be recorded in the CRF. 2 Patients not achieving remission within 6 months to be withdrawn from trial drug regimen and will be treated according to local practice. They will remain under trial follow up.
3.7. Adverse events
1 Adverse effects will be actively sought and recorded in CRFs at each evaluation (see section 4.5 and TMF). 2 Unexpected, severe adverse events attributable to study medication must be reported within 24 hours to trial management committee. (see TMF and section 4.5 for full details).
3.8. Statistical analysis
Primary end points will be assessed upon trial completion at 2 years. However interim analyses will be performed: (a) When 30 patients have completed 6 weeks trial participation to assess (1) treatment response (BVAS fall of > 50% baseline). (2) safety (adverse events CTCAE grade 3 or greater) and (b) When 40 patients have completed 6 months trial participation to assess (1) remission (BVAS 0 for 2 months by 6 months) (2) safety (adverse events CTCAE grade 3 or greater)Primary end point confidence Intervals. A total of 30 patients will receive rituximab. The expected sustained remission rate for rituximab is 86%, based on the results of former studies. The 95% confidence interval for a sustained remission rate of 86% is 70.3%-94.7% when the sample size is 30. The expected response rate of 86% is considered clinically significant as patients with active newly diagnosed generalised AASV without 3-6 months of cyclophosphamide are conventionally expected to experience disease progression (worsening of clinical signs and symptoms). The expected sustained remission rate in the control group is 75%. Analyses on the 40 patients should be considered exploratory.
3.9. Duration: 3 years: 6 months recruitment, two year follow-up per patient and 6 month analyses.
Visit the EUVAS website for details.
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