Rituximab And Hyaluronidase Human
Rituximab And Hyaluronidase Human Uses, Dosage, Side Effects, Food Interaction and all others data.
Hyaluronidase is a dispersion agent, which modifies the permeability of connective tissue through the hydrolysis of hyaluronic acid, a polysaccharide found in the intercellular ground substance of connective tissue, and of certain specialized tissues, such as the umbilical cord and vitreous humor. Hyaluronic acid is also present in the capsules of type A and C hemolytic streptococci. Hyaluronidase hydrolyzes hyaluronic acid by splitting the glucosaminidic bond between C1 of an N-acetylglucosamine moiety and C4 of a glucuronic acid moiety. This temporarily decreases the viscosity of the cellular cement and promotes dispersion of injected fluids or of localized transudates or exudates, thus facilitating their absorption. Hyaluronidase cleaves glycosidic bonds of hyaluronic acid and, to a variable degree, some other acid mucopolysaccharides of the connective tissue. The activity is measured in vitro by monitoring the decrease in the amount of an insoluble serum albumin-hyaluronic acid complex as the enzyme cleaves the hyaluronic acid component.
Rituximab is a chimeric monoclonal antibody to CD20 antigen which regulates cell cycle initiation. It binds to the antigen on the cell surface, activating complement-dependent B-cell cytotoxicity; and to human Fc receptors, mediating cell killing through an antibody-dependent cellular toxicity.
Duration: Detectable in serum 3-6 mth after completion of therapy; B-cell recovery 6-12 mth following completion of therapy.
Rituximab binds to the CD20 antigen, which is predominantly expressed on mature B cells and on >90% of B-cell non-Hodgkin's lymphomas . The antibody leads to selective killing of B-cells. The following are the pharmacodynamic outcomes for various conditions, including non- Hodgkin's Lymphoma :
Non-Hodgkin’s Lymphoma (NHL)In Non-Hodgkin's Lymphoma patients, the administration of rituximab led to the depletion of circulating and tissue-based B cells. Among 166 patients in Study 1, circulating CD19-positive B cells were depleted within the first three weeks, showing sustained depletion for up to 6-9 months post-treatment in 83% of treated patients. B-cell recovery began at approximately 6 months and median B-cell levels returned to normal by 12 months following the completion of treatment . There were sustained and statistically significant decreases in serum IgM and IgG levels measured from 5-11 months following rituximab administration; 14% of patients showed IgM and/or IgG serum levels below the normal range .
Rheumatoid ArthritisIn rheumatoid arthritis (RA) patients, treatment with rituximab induced the depletion of peripheral B lymphocytes, with the majority of patients showing near-complete depletion (CD19 counts below the lower limit of quantification, 20 c-lls/μl) within 2 weeks after the first dose of rituximab. The majority of treated patients showed peripheral B-cell depletion, sustained for a minimum of 6 months. A small percentage of patients (~4%) had peripheral B-cell depletion that was sustained for more than 3 years after one course of treatment. Total serum immunoglobulin levels, IgM, IgG, and IgA were decreased at 6 months with the greatest change observed in IgM. At Week 24 of the first cycle of rituximab treatment, small percentages of patients experienced decreases in IgM (10%), IgG (2.8%), and IgA (0.8%) levels below the lower limit of normal (LLN). When rituximab was administered to RA patients during repeated rituximab treatment, 23.3%, 5.5%, and 0.5% of patients experienced decreases in IgM, IgG, and IgA concentrations below LLN at any time after receiving rituximab, respectively. The clinical consequences of decreases in immunoglobulin levels in RA patients treated with rituximab are not clear at this time. Treatment with rituximab in patients with RA was associated with a decreased level of several biologic markers of inflammation such as interleukin-6 (IL-6), C-reactive protein (CRP), serum amyloid protein (SAA), S100 A8/S100 A9 heterodimer complex (S100 A8/9), anti-citrullinated peptide (anti-CCP), and RF and was found to decrease disease symptoms .
| Trade Name | Rituximab And Hyaluronidase Human |
| Generic | Hyaluronidase + rituximab |
| Type | Subcutaneous |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Hyaluronidase recombinant is a tissue permeability modifier used as an adjuvant-
- In subcutaneous fluid administration for achieving hydration
- To increase the dispersion and absorption of other injected drugs
- In subcutaneous urography for improving resorption of radiopaque agents
Non-Hodgkin's Lymphoma (NHL): Rituximab is used for the treatment of patients with-
- Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent
- Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to Rituxan in combination with chemotherapy, as single-agent maintenance therapy.
- Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line CVP chemotherapy
- Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens
Chronic Lymphocytic Leukemia (CLL): Rituximab is used, in combination with fludarabine and cyclophosphamide (FC), for the treatment of patients with previously untreated and previously treated CD20-positive CLL.
Rheumatoid Arthritis (RA): Rituximab in combination with methotrexate is used for the treatment of adult patients with moderately- to severely- active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.
Granulomatos Is With Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA): Rituximab, in combination with glucocorticoids, is used for the treatment of adult patients with Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) andMicroscopic Polyangiitis (MPA).
Rituximab And Hyaluronidase Human is also used to associated treatment for these conditions: Parenteral rehydration therapy, Parenteral drug administration, Subcutaneous urographyChronic Lymphocytic Leukaemia (CLL), Granulomatosis With Polyangiitis, Granulomatosis With Polyangiitis (GPA), Microscopic Polyangiitis, Microscopic Polyangiitis (MPA), Non-Hodgkin's Lymphoma (NHL), Pemphigus Vulgaris (PV), Moderate Rheumatoid arthritis, Moderate to severe pemphigus vulgaris, Severe Rheumatoid arthritis
How Rituximab And Hyaluronidase Human works
Hyaluronidase cleaves hyaluronic acid at the glucosaminidic bond between C1 of glucosamine and C4 of glucuronic acid. Hyaluronic acid is a key component of the extracellular matrix. Injection of hyaluronidase with other fluids, drugs, or radiopaque agents improves the ability of these other compounds to permeate the extracellular space more easily.
Rituximab is a monoclonal antibody that targets the CD20 antigen, which is expressed on the surface of pre-B and mature B-lymphocytes , , , . After binding to CD20, rituximab mediates B-cell lysis (or breakdown). The possible mechanisms of cell lysis include complement dependent cytotoxicity (CDC) and antibody dependent cell-mediated cytotoxicity (ADCC) .
Rituximab belongs to the immunoglobulin G1 (IgG1) sub-class, consisting of a murine variable region (Fab region) and a human constant region (Fc region). The Fab region has variable sections that define a specific target antigen, allowing the antibody to attract and secure its exclusive antigen, specifically the binding of rituximab (IgG1) to CD20 on pre-B and mature B lymphocytes. The Fc region is the tail end of the antibody that communicates with cell surface receptors to activate the immune system, in this case, a sequence of events leading to the depletion of circulating B lymphocytes by complement-dependent cell lysis, antibody-dependent cellular cytotoxicity, as well as apoptosis .
In regards to the mechanism of action in rheumatoid arthritis, B cells are thought to play a role in the pathogenesis of rheumatoid arthritis (RA) and the associated condition of chronic synovitis. B cells may act at various sites in the autoimmune/inflammatory process, including through production of rheumatoid factor (RF) and other autoantibodies, antigen presentation, T-cell activation, and/or the production of proinflammatory cytokines . The administration of rituximab in this condition has been shown to result in significant clinical and symptomatic improvements , .
Dosage
Rituximab And Hyaluronidase Human dosage
Inject 150 units Hyaluronidase recombinant prior to subcutaneous fluid administration. It will facilitate absorption of 1,000 mL or more of solution. The dosage of subcutaneous fluids administered is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. The rate and volume of subcutaneous fluid administration should not exceed those employed for intravenous infusion
Increasing dispersion and absorption of injected drugs: Add 50-300 units (most typically 150 U) Hyaluronidase recombinant to the injection solution.
Subcutaneous Urography: Inject 75 units Hyaluronidase recombinant subcutaneously over each scapula, followed by injection of the contrast medium at the same sites
Intravenous (Adult)-
Non-Hodgkin's lymphoma, Refractory or relapsed follicular lymphoma: As a single agent, 375 mg/m2 infusion once wkly, for 4 doses at an initial rate of 50 mg/hr. May increase by 50 mg/hr every 30 min. If tolerated, subsequent infusions can be started at 100 mg/hr and increased by 100 mg/hr every 30 min. Max rate: 400 mg/hr. When used with CVP (cyclophosphamide, vincristine and prednisolone) for follicular lymphoma or CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) for diffuse large B-cell lymphoma, 375 mg/m2 given on day 1 of the chemotherapy cycle after corticosteroid regimen, for up to 8 cycles. For patients who were treated with 6-8 cycles of CVP chemotherapy and have not progressed, 375 mg/m2 may be given once wkly for 4 doses, may repeat every 6 mth, for up to 16 doses. Maintenance: 375 mg/m2 given once every 3 mth (those who have responded to induction chemotherapy), once every 2 mth initiated 2 mth after the last dose of induction chemotherapy (previously untreated) for a max period of 2 yr.
Chronic lymphocytic leukaemia: 375 mg/m2, given on the day prior to chemotherapy in cycle 1, followed by 500 mg/m2 on day 1 (every 28 days) of cycles 2-6.
Rheumatoid arthritis: Given as two 1 g IV infusion doses, separated by 2 wk and in combination with methotrexate. Corticosteroids may be given before each infusion to minimise the risk and severity of infusion reactions.
Dilute the appropriate dose with sodium chloride 0.9% or glucose 5% to a final concentration of between 1 and 4 mg/mL.
Side Effects
The following adverse reactions have been identified during post-approval use of hyaluronidase products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The most frequently reported adverse reactions have been mild local injection site reactions such as erythema and pain. Hyaluronidase has been reported to enhance the adverse reactions associated with co-administered drug products. Edema has been reported most frequently in association with subcutaneous fluid administration. Allergic reactions (urticaria or angioedema) have been reported in less than 0.1% of patients receiving hyaluronidase. Anaphylactic-like reactions following retrobulbar block or intravenous injections have occurred, rarely.
Reactivation of hepatitis B virus. Fever and rigors. Pruritus, skin rashes, dyspnoea, bronchospasm, angioedema, transient hypotension, and flushing, asthenia, headache, rhinitis, thrombocytopenia, neutropenia, anaemia, abdominal pain, bowel obstruction, and perforation. Exacerbation of heart failure and angina pectoris. Reversible interstitia
Toxicity
Data regarding overdose of hyaluronidase is not readily available. In the even of an overdose, treat patients with symptomatic and supportive measures.
Oral LD50: 27 mg/kg (mouse and rat)
Inhalation LD50: 32 mg/m3 (mouse) and 37 mg/m3 (rat)
Skin LD50: 20 mg/kg (rabbit) and 50 mg/kg (rat)
Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of rituximab or to determine potential effects on fertility in males or females .
Embryo-Fetal toxicity: Can cause neonatal harm. Advise of potential risk to neonates and use of effective contraception .
Precaution
Spread of Localized Infection: Hyaluronidase should not be injected into or around an infected or acutely inflamed area because of the danger of spreading a localized infection. Hyaluronidase should not be used to reduce the swelling of bites or stings.
Ocular Damage: Hyaluronidase should not be applied directly to the cornea. It is not for topical use.
Enzyme Inactivation with Intravenous Administration: Hyaluronidase recombinant should not be administered intravenously. Its effects relative to dispersion and absorption of other drugs are not produced when it is administered intravenously because the enzyme is rapidly inactivated.
Extensive tumour burden, pulmonary insufficiency or pulmonary tumour infiltration; history of cardiac disease. Pregnancy.
Interaction
It is recommended that appropriate references be consulted regarding physical or chemical incompatibilities before adding Hyaluronidase recombinant to a solution containing another drug.
Increased risk of renal toxicity with cisplatin.
Volume of Distribution
Data regarding the volume of distribution of hyaluronidase are not readily available.
3.1 L in Rheumatoid Arthritis
4.5 L in Granulomatosis with polyangitis and microscopic polyangitis
Elimination Route
Data regarding the absorption of hyaluronidase are not readily available.
Following the administration of 2 doses of rituximab in patients with rheumatoid arthritis (RA), the mean (± S.D.; % CV) concentrations after the first infusion (Cmax first) and second infusion (Cmax second) were : 157 ( ± 46; 29%) and 183 ( ± 55; 30%) mcg/mL, and 318 ( ± 86; 27%) and 381 ( ± 98; 26%) mcg/mL for the 2 × 500 mg and 2 × 1000 mg doses, respectively .
Half Life
Hyaluronidase has a half life of two minutes, but a duration of action of 24-48 hours due to its high potency.
Non-Hodgkin's Lymphoma: Based on a population pharmacokinetic analysis of data from 298 Non-Hodgkin's Lymphoma (NHL) patients who received rituximab once weekly or once every three weeks, the estimated median terminal elimination half-life was 22 days (range, 6.1 to 52 days) .
Rheumatoid Arthritis: Mean terminal elimination half-life was 18.0 days in patients with rheumatoid arthritis Based on a population pharmacokinetic analysis of data from 2005 RA patients who received rituximab .
Chronic Lymphocytic Leukemia (CLL): Pharmacokinetics were studied in 21 patients with CLL receiving rituximab according to the recommended dose and schedule. The estimated median terminal half-life of rituximab was 32 days (range, 14-62 days) .
Granulomatosis with Polyangitis and Microscopic Polyangitis: Based on the population pharmacokinetic analysis of data in 97 GPA and MPA patients who received 375 mg/m2 rituximab once weekly by intravenous infusion for four weeks, the estimated median terminal elimination half-life was 23 days (range, 9 to 49 days) .
Clearance
Data regarding the clearance of hyaluronidase are not readily available.
Rheumatoid Arthritis: 0.335 L/day
Granulomatosis with Polyangitis and Microscopic Polyangitis: 0. 312 L/day
Patients with higher CD19-positive cell counts or larger measurable tumor lesions at pretreatment had a higher clearance .
Elimination Route
After nonspecific proteolysis, the amino acids from protein drugs are reused for protein synthesis or further broken down and eliminated by the kidneys.
Likely eliminated through the reticuloendothelial system .
Pregnancy & Breastfeeding use
Pregnancy Category C. It is also not known whether Hyaluronidase recombinant can cause fetal harm when administered to a pregnant woman. Hyaluronidase recombinant should be given to a pregnant woman only if clearly needed.
Nursing Mothers: It is not known whether hyaluronidase is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when hyaluronidase is administered to a nursing woman
Pregnancy Category C. Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.
Contraindication
Hyaluronidase recombinant is contraindicated in patients with known hypersensitivity to hyaluronidase or any of the excipients in Hyaluronidase recombinant. A preliminary skin test for hypersensitivity to Hyaluronidase recombinant can be performed. The skin test is made by an intradermal injection of approximately 0.02 mL (3 Units) of a 150 Unit/mL solution. A positive reaction consists of a wheal with pseudopods appearing within 5 minutes and persisting for 20 to 30 minutes and accompanied by localized itching. Transient vasodilation at the site of the test, i.e., erythema, is not a positive reaction. Discontinue Hyaluronidase recombinant if sensitization occurs.
Hypersensitivity to murine proteins. Patients with active, severe infections. Severely immunocompromised state. Concomitant use with live viral vaccines. Lactation.
Special Warning
Pediatric Use: Clinical hydration requirements for children can be achieved through administration of subcutaneous fluids facilitated with Hyaluronidase recombinant.
Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger adult patients.
Storage Condition
Store unopened in a refrigerator at 2° to 8°C. DO NOT FREEZE.
Store between 2-8° C.
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