Limitation of Use

SYLVANT was not studied in patients with MCD who are HIV positive or HHV-8 positive because SYLVANT did not bind to virally produced IL-6 in a nonclinical study.

2.1 Dosage

SYLVANT 11 mg/kg is given over 1 hour as an intravenous infusion administered every 3 weeks until treatment failure.

Perform hematology laboratory tests prior to each dose of SYLVANT therapy for the first 12 months and every 3 dosing cycles thereafter. If treatment criteria outlined in Table 1 are not met, consider delaying treatment with SYLVANT. Do not reduce dose.

Do not administer SYLVANT to patients with severe infections until the infection resolves.

Discontinue SYLVANT in patients with severe infusion related reactions, anaphylaxis, severe allergic reactions, or cytokine release syndromes. Do not reinstitute treatment.

2.2 Instructions for Preparation and Administration

Use aseptic technique for reconstitution and preparation of dosing solution.

1. Calculate the dose (mg), total volume (mL) of reconstituted SYLVANT solution required and the number of vials needed. A 21-gauge 1½ inch needle is recommended for preparation. Infusion bags (250 mL) must contain Dextrose 5% in Water and must be made of polyvinyl chloride (PVC), or polyolefin (PO), or polypropylene (PP), or polyethylene (PE). Alternatively PE bottles may be used.

2. Allow the vial(s) of SYLVANT to come to room temperature over approximately 30 minutes. SYLVANT should remain at room temperature for the duration of the preparation.

3. Aseptically reconstitute each SYLVANT vial as instructed in Table 2.

Gently swirl the reconstituted vials to aid the dissolution of the lyophilized powder. DO NOT SHAKE or SWIRL VIGOROUSLY. Do not remove the contents until all of the solids have been completely dissolved. The lyophilized powder should dissolve in less than 60 minutes.

Once reconstituted, and prior to further dilution, inspect the vials for particulates and discoloration. Do not use if particles or solution discoloration are present or if visibly opaque. The reconstituted product should be kept for no more than two hours prior to addition into the infusion bag.

4. Dilute the reconstituted SYLVANT solution dose to 250 mL with sterile Dextrose 5% in Water by withdrawing a volume equal to the total calculated volume of reconstituted SYLVANT from the Dextrose 5% in Water, 250 mL bag. Slowly add the total calculated volume (mL) of reconstituted SYLVANT solution to the Dextrose 5% in Water infusion bag. Gently invert the bag to mix the solution.

5. Administer the diluted SYLVANT solution in 5% Dextrose in Water 250 mL by intravenous infusion over a period of 1 hour using administration sets lined with PVC, or polyurethane (PU), or PE, containing a 0.2-micron inline polyethersulfone (PES) filter. The infusion should be completed within 4 hours of the dilution of the reconstituted solution to the infusion bag.

6. Do not infuse SYLVANT concomitantly in the same intravenous line with other agents.

7. Do not store any unused portion of the reconstituted product or of the infusion solution. Waste material should be disposed of in accordance with local requirements.

 5.1 Concurrent Active Severe Infections

Do not administer SYLVANT to patients with severe infections until the infection resolves. SYLVANT may mask signs and symptoms of acute inflammation including suppression of fever and of acute Phase reactants such as C-reactive protein (CRP). Monitor patients receiving SYLVANT closely for infections. Institute prompt anti-infective therapy and do not administer further SYLVANT until the infection resolves.

5.2 Vaccinations

Do not administer live vaccines to patients receiving SYLVANT because IL-6 inhibition may interfere with the normal immune response to new antigens.

5.3 Infusion Related Reactions and Hypersensitivity

Stop the infusion of SYLVANT if the patient develops signs of anaphylaxis. Discontinue further therapy with SYLVANT.

Stop the infusion if the patient develops a mild to moderate infusion reaction. If the reaction resolves, the SYLVANT infusion may be restarted at a lower infusion rate. Consider medication with antihistamines, acetaminophen, and corticosteroids. Discontinue SYLVANT if the patient does not tolerate the infusion following these interventions [see Adverse Reactions (6)].

Administer SYLVANT in a setting that provides resuscitation equipment, medication, and personnel trained to provide resuscitation.

5.4 Gastrointestinal Perforation

Gastrointestinal (GI) perforation has been reported in clinical trials although not in MCD trials. Use with caution in patients who may be at increased risk for GI perforation. Promptly eva luate patients presenting with symptoms that may be associated or suggestive of GI perforation.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The most common adverse reactions (> 10% compared to placebo) during treatment with SYLVANT in the MCD clinical trial were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infection.

The data presented below in Table 3 were collected from Study 1. Study 1, in MCD, was an international, multicenter, randomized Phase 2 study of every 3 week infusions comparing SYLVANT and best supportive care (BSC) to placebo and BSC. There were 53 patients randomized to the SYLVANT arm at a dose of 11 mg/kg and 26 patients randomized to the placebo arm. Of the 26 placebo-treated patients, 13 patients subsequently crossed-over to receive SYLVANT. The median age was 48 years (range 20 to 78), 66% male, 48% Asian, 39% White, 4% Black or African American, 7% other. The patients randomized to SYLVANT received a median of 19 infusions (range 1 to 50) compared to patients randomized to placebo who received a median of 8 infusions (range 2 to 32). To control for disparate exposure between arms, Table 3 reports the per patient incidence of adverse reactions that occurred during the first 8 infusions. Adverse reactions that occurred >3% in the SYLVANT arm are presented.

Table 3: Per Patient Incidence of Common Adverse Reactions in Study 1 During Initial 8 Infusions

	SYLVANT+BSC* n=53		Placebo+BSC n=26
	All Grades	Grades 3–4	All Grades	Grades 3–4
* Best Supportive Care † Anaphylactic reaction
Skin disorders
Rash (rash, rash generalized, rash maculo-papular, rash popular and rash pruritic)	15 (28%)	1 (2%)	3 (12%)	0
Pruritis	15 (28%)	0	2 (8%)	0
Skin hyperpigmentation	2 (4%)	0	0	0
Eczema	2 (4%)	0	0	0
Psoriasis	2 (4%)	0	0	0
Dry skin	2 (4%)	0	0	0
Infections
Lower respiratory tract	4 (8%)	2 (4%)	1 (4%)	1 (4%)
Upper respiratory tract	14 (26%)	1 (2%)	4 (15%)	1 (4%)
Blood and lymphatic system disorders
Thrombocytopenia	5 (9%)	2 (4%)	1 (4%)	1 (4%)
General disorders
Edema (general and localized)	14 (26%)	4 (8%)	7 (27%)	0
Gastrointestinal disorders
Constipation	4 (8%)	0	1 (4%)	0
Metabolism
Hypertriglyceridemia	4 (8%)	0	0	0
Hypercholesterolemia	2 (4%)	0	0	0
Hyperuricemia	6 (11%)	1 (2%)	0	0
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	4 (8%)	0	1 (4%)	0
Renal and urinary disorders
Renal impairment	4 (8%)	0	0	0
Nervous system disorders
Headache	4 (8%)	0	1 (4%)	0
Investigations
Weight increased	10 (19%)	1 (2%)	0	0
Vascular disorders
Hypotension	2 (4%)	1 (2%)†
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