Talvey Injection Dosage

Generic name: TALQUETAMAB 3mg in 1.5mL
Dosage form: injection
Drug class: Miscellaneous antineoplastics

Medically reviewed by Drugs.com. Last updated on Aug 18, 2023.

Important Dosing Information

Administer TALVEY subcutaneously according to the step-up dosing schedule in Tables 1 and 2 to reduce the incidence and severity of cytokine release syndrome (CRS) [see Dosage and Administration (2.2)] .

Administer pretreatment medications prior to each dose of TALVEY in the step-up dosing schedule as recommended [see Dosage and Administration (2.2, 2.3)].

TALVEY should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and neurologic toxicity including immune effector cell-associated neurotoxicity syndrome (ICANS) [see Warnings and Precautions (5.1, 5.2)] .

Due to the risk of CRS and neurologic toxicity, including ICANS, patients should be hospitalized for 48 hours after administration of all doses within the TALVEY step-up dosing schedule [see Dosage and Administration (2.5)and Warnings and Precautions (5.1, 5.2)] .

Recommended Dosage

For subcutaneous injection.

Administer pretreatment medications prior to each dose of TALVEY in the step-up dosing schedule [see Dosage and Administration (2.3)] .

Administer TALVEY subcutaneously on a weekly or biweekly (every 2 weeks) dosing schedule according to Table 1 or Table 2. Continue treatment until disease progression or unacceptable toxicity.

Table 1: TALVEY Weekly Dosing Schedule
Dosing schedule	Day	Dose *
* Based on actual body weight. † Dose may be administered between 2 to 4 days after the previous dose and may be given up to 7 days after the previous dose to allow for resolution of adverse reactions. ‡ Maintain a minimum of 6 days between weekly doses.
Step-up dosing schedule	Day 1	Step-up dose 1	0.01 mg/kg
	Day 4 †	Step-up dose 2	0.06 mg/kg
	Day 7 †	First treatment dose	0.4 mg/kg
Weekly dosing schedule	One week after first treatment dose and weekly thereafter ‡	Subsequent treatment doses	0.4 mg/kg once weekly

Table 2: TALVEY Biweekly (Every 2 Weeks) Dosing Schedule
Dosing schedule	Day	Dose *
* Based on actual body weight. † Dose may be administered between 2 to 4 days after the previous dose and may be given up to 7 days after the previous dose to allow for resolution of adverse reactions. ‡ Dose may be administered between 2 to 7 days after step-up dose 3. § Maintain a minimum of 12 days between biweekly (every 2 weeks) doses.
Step-up dosing schedule	Day 1	Step-up dose 1	0.01 mg/kg
	Day 4 †	Step-up dose 2	0.06 mg/kg
	Day 7 †	Step-up dose 3	0.4 mg/kg
	Day 10 ‡	First treatment dose	0.8 mg/kg
Biweekly (every 2 weeks) dosing schedule	Two weeks after first treatment dose and every 2 weeks thereafter §	Subsequent treatment doses	0.8 mg/kg every 2 weeks

Recommended Pretreatment Medications

Administer the following pretreatment medications 1 to 3 hours before each dose of TALVEY in the step-up dosing schedule to reduce the risk of CRS [see Warnings and Precautions (5.1)] .

Corticosteroid (oral or intravenous dexamethasone, 16 mg or equivalent)
Antihistamines (oral or intravenous diphenhydramine, 50 mg or equivalent)
Antipyretics (oral or intravenous acetaminophen, 650 mg to 1,000 mg or equivalent)

Administration of pretreatment medications may be required for subsequent doses for patients who repeat doses within the TALVEY step-up dosing schedule due to dose delays (see Table 3or Table 4) or for patients who experienced CRS (see Table 5).

Dosage Delays

If a dose of TALVEY is delayed, restart therapy based on the recommendations in Table 3 and Table 4 and resume weekly or biweekly (every 2 weeks) dosing schedule accordingly [see Dosage and Administration (2.1)] ; if a dose is delayed by more than 28 days for an adverse reaction, evaluate the benefit-risk of restarting TALVEY. Administer pretreatment medications prior to restarting TALVEY and monitor patients following administration of TALVEY [see Dosage and Administration (2.2)].

Table 3: Recommendations for Restarting TALVEY after Dose Delay – Weekly Dosing Schedule
Last Dose Administered	Time from Last Dose Administered	TALVEY Recommendation *
* Administer pretreatment medications prior to restarting TALVEY. After restarting TALVEY, resume weekly dosing schedule accordingly [see Dosage and Administration (2.2)] .
0.01 mg/kg	More than 7 days	Restart TALVEY step-up dosing schedule at step-up dose 1 (0.01 mg/kg).
0.06 mg/kg	8 to 28 days	Repeat step-up dose 2 (0.06 mg/kg) and continue TALVEY step-up dosing schedule.
0.06 mg/kg	More than 28 days	Restart TALVEY step-up dosing schedule at step-up dose 1 (0.01 mg/kg).
0.4 mg/kg	8 to 28 days	Continue TALVEY dosing schedule at treatment dose (0.4 mg/kg weekly).
	29 to 56 days	Restart TALVEY step-up dosing schedule at step-up dose 2 (0.06 mg/kg).
	More than 56 days	Consider permanent discontinuation. If restarting TALVEY, begin with the step-up dosing schedule at step-up dose 1 (0.01 mg/kg).

Table 4: Recommendations for Restarting TALVEY after Dose Delay – Biweekly (Every 2 Weeks) Dosing Schedule
Last Dose Administered	Time from Last Dose Administered	TALVEY Recommendation *
* Administer pretreatment medications prior to restarting TALVEY. After restarting TALVEY, resume biweekly (every 2 weeks) dosing schedule accordingly [see Dosage and Administration (2.2)] .
0.01 mg/kg	More than 7 days	Restart TALVEY step-up dosing schedule at step-up dose 1 (0.01 mg/kg).
0.06 mg/kg	8 to 28 days	Repeat step-up dose 2 (0.06 mg/kg) and continue TALVEY step-up dosing schedule.
0.06 mg/kg	More than 28 days	Restart TALVEY step-up dosing schedule at step-up dose 1 (0.01 mg/kg).
0.4 mg/kg	8 to 28 days	Repeat step-up dose 3 (0.4 mg/kg) and continue TALVEY step-up dosing schedule.
	29 to 56 days	Restart TALVEY step-up dosing schedule at step-up dose 2 (0.06 mg/kg).
	More than 56 days	Consider permanent discontinuation. If restarting TALVEY, begin with the step-up dosing schedule at step-up dose 1 (0.01 mg/kg).
0.8 mg/kg	15 to 28 days	Continue TALVEY dosing schedule at treatment dose (0.8 mg/kg every 2 weeks).
	29 to 56 days	Restart TALVEY step-up dosing schedule at step-up dose 3 (0.4 mg/kg).
	More than 56 days	Consider permanent discontinuation. If restarting TALVEY, begin with the step-up dosing schedule at step-up dose 1 (0.01 mg/kg).

Dosage Modifications for Adverse Reactions

Dose delays may be required to manage toxicities related to TALVEY [see Warnings and Precautions (5)] .

See Table 5, Table 6, and Table 7for recommended actions for the management of CRS, ICANS, and neurologic toxicity. See Table 8for recommended dose modifications for other adverse reactions.

Cytokine Release Syndrome (CRS)

Identify CRS based on clinical presentation [see Warnings and Precautions (5.1)] . Evaluate and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, withhold TALVEY until CRS resolves or permanently discontinue based on severity, manage according to the recommendations in Table 5, consider further management per current practice guidelines. Administer supportive therapy for CRS, which may include intensive care for severe or life-threatening CRS. Consider laboratory testing to monitor for disseminated intravascular coagulation (DIC), hematology parameters, as well as pulmonary, cardiac, renal, and hepatic function.

Table 5: Recommendations for Management of CRS
CRS Grade *	Presenting Symptoms	Actions
* Based on American Society for Transplantation and Cellular Therapy (ASTCT) grading for CRS (Lee et al 2019). † Attributed to CRS. Fever may not always be present concurrently with hypotension or hypoxia as it may be masked by interventions such as antipyretics or anticytokine therapy (e.g., corticosteroids). ‡ See Table 3 and Table 4 for recommendations on restarting TALVEY after dose delays for adverse reactions [see Dosage and Administration (2.4)]. § Low-flow nasal cannula is ≤6 L/min, and high-flow nasal cannula is >6 L/min.
Grade 1	Temperature ≥100.4°F (38°C) †	Withhold TALVEY until CRS resolves. ‡ Administer pretreatment medication prior to next dose.
Grade 2	Temperature ≥100.4°F (38°C) †with either: Hypotension responsive to fluids and not requiring vasopressors, or Oxygen requirement of low-flow nasal cannula §or blow-by.	Withhold TALVEY until CRS resolves. Administer pretreatment medications prior to next dose. Patients should be hospitalized for 48 hours following the next dose. ‡
Grade 3	Temperature ≥100.4°F (38°C) †with either: Hypotension requiring one vasopressor, with or without vasopressin, or Oxygen requirement of high-flow nasal cannula §, facemask, non-rebreather mask, or Venturi mask	Duration less than 48 hours Withhold TALVEY until CRS resolves. Provide supportive therapy, which may include intensive care. Administer pretreatment medications prior to the next dose. Patients should be hospitalized for 48 hours following the next dose. ‡
Grade 3		Recurrent or duration greater than or equal to 48 hours Permanently discontinue TALVEY. Provide supportive therapy, which may include intensive care.
Grade 4	Temperature ≥100.4°F (38°C) †with either: Hypotension requiring multiple vasopressors (excluding vasopressin). Or, oxygen requirement of positive pressure (e.g., continuous positive airway pressure [CPAP], bilevel positive airway pressure [BiPAP], intubation, and mechanical ventilation)	Permanently discontinue TALVEY. Provide supportive therapy, which may include intensive care.

Neurologic Toxicity, including ICANS

At the first sign of neurologic toxicity, including ICANS, withhold TALVEY and consider neurology evaluation. Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care, for severe or life-threatening neurologic toxicities, including ICANS [see Warnings and Precautions (5.2)] . Manage ICANS and neurologic toxicity according to the recommendations in Table 6 and Table 7 and consider further management per current practice guidelines.

Table 6: Recommendations for Management of ICANS
Grade *	Presenting Symptoms †	Actions
* Based on ASTCT 2019 grading for ICANS. † Management is determined by the most severe event, not attributable to any other cause. ‡ If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE) Assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (name 3 objects, e.g., point to clock, pen, button = 3 points); Following Commands (e.g., "show me 2 fingers" or "close your eyes and stick out your tongue" = 1 point); Writing (ability to write a standard sentence = 1 point; and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points. § Attributable to no other cause. ¶ See Table 3 and Table 4 for recommendations on restarting TALVEY after dose delays for adverse reactions [see Dosage and Administration (2.4)]. # All references to dexamethasone administration are dexamethasone or equivalent.
Grade 1	ICE score 7–9 ‡, or depressed level of consciousness §: awakens spontaneously.	Withhold TALVEY until ICANS resolves. ¶ Monitor neurologic symptoms, and consider consultation with neurologist and other specialists for further evaluation and management. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.
Grade 2	ICE score 3–6 ‡, or depressed level of consciousness §: awakens to voice.	Withhold TALVEY until ICANS resolves. Administer dexamethasone #10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. Patients should be hospitalized for 48 hours following the next dose of TALVEY [see Dosage and Administration (2.1)] . ¶
Grade 3	ICE score 0–2 ‡, (If ICE score is 0, but the patient is arousable (e.g., awake with global aphasia) and able to perform assessment) or depressed level of consciousness §: awakens only to tactile stimulus, or seizures §, either: any clinical seizure, focal or generalized, that resolves rapidly, or non-convulsive seizures on electroencephalogram (EEG) that resolve with intervention, or raised intracranial pressure: focal/local edema on neuroimaging §.	First Occurrence of Grade 3 ICANS: Withhold TALVEY until ICANS resolves. Administer dexamethasone #10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. Provide supportive therapy, which may include intensive care. Patients should be hospitalized for 48 hours following the next dose of TALVEY [see Dosage and Administration (2.1)] . ¶ Recurrent Grade 3 ICANS: Permanently discontinue TALVEY. Administer dexamethasone #10 mg intravenously and repeat dose every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. Provide supportive therapy, which may include intensive care.
Grade 3
Grade 4	ICE score 0 ‡ (Patient is unarousable and unable to perform ICE assessment) or depressed level of consciousness §: either: patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or stupor or coma, or seizures §, either: life-threatening prolonged seizure (>5 minutes), or repetitive clinical or electrical seizures without return to baseline in between, or motor findings §: deep focal motor weakness such as hemiparesis or paraparesis, or raised intracranial pressure/cerebral edema §, with signs/symptoms such as: diffuse cerebral edema on neuroimaging, or decerebrate or decorticate posturing, or cranial nerve VI palsy, or papilledema, or Cushing's triad.	Permanently discontinue TALVEY. Administer dexamethasone #10 mg intravenously and repeat dose every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Alternatively, consider administration of methylprednisolone 1,000 mg per day intravenously and continue methylprednisolone 1,000 mg per day intravenously for 2 or more days. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. Provide supportive therapy, which may include intensive care.

Table 7: Recommendations for Management of Neurologic Toxicity (excluding ICANS)
Adverse Reaction	Severity *	Actions
* Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. † See Table 3 and Table 4 for recommendations on restarting TALVEY after dose delays for adverse reactions [see Dosage and Administration (2.4)] .
Neurologic Toxicity *(excluding ICANS)	Grade 1	Withhold TALVEY until neurologic toxicity symptoms resolve or stabilize. †
	Grade 2 Grade 3 (First occurrence)	Withhold TALVEY until neurologic toxicity symptoms improve to Grade 1 or less. † Provide supportive therapy.
	Grade 3 (Recurrent) Grade 4	Permanently discontinue TALVEY. Provide supportive therapy, which may include intensive care.

Other Adverse Reactions

The recommended dose modifications for other adverse reactions are provided in Table 8.

Table 8: Recommended Dose Modifications for Other Adverse Reactions
Adverse Reaction	Severity	Dose Modification
* See Table 3 and Table 4 for recommendations on restarting TALVEY after dose delays for adverse reactions [see Dosage and Administration (2.4)]. † For Grade 3 or 4 infection, if TALVEY is withheld for more than 28 days, restart step-up dosing when infection improves to Grade 1 or better. ‡ Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03.
Oral Toxicity and Weight Loss [see Warnings and Precautions (5.4)]	Grade 1–2	Provide supportive care. Consider withholding TALVEY if not responsive to supportive care. *
	Grade 3	Withhold TALVEY until resolution to Grade 1 or better and provide supportive care. *
	Grade 4	Permanently discontinue TALVEY.
Infections [see Warnings and Precautions (5.5)]	All Grades	Withhold TALVEY in the step-up phase in patients until infection resolves.
	Grade 3	Withhold TALVEY during the treatment phase until infection improves to Grade 1 or better within 28 days. †
	Grade 4	Consider permanent discontinuation of TALVEY. If TALVEY is not permanently discontinued, withhold subsequent treatment doses of TALVEY (i.e., doses administered after TALVEY step-up dosing schedule) until adverse reaction improves to Grade 1 or better. †
Cytopenias [see Warnings and Precautions (5.6)]	Absolute neutrophil count less than 0.5 × 10 9/L	Withhold TALVEY until absolute neutrophil count is 0.5 × 10 9/L or higher. *
	Febrile neutropenia	Withhold TALVEY until absolute neutrophil count is 1.0 × 10 9/L or higher and fever resolves. *
	Hemoglobin less than 8 g/dL	Withhold TALVEY until hemoglobin is 8 g/dL or higher. *
	Platelet count less than 25,000/mcL Platelet count between 25,000/mcL and 50,000/mcL with bleeding	Withhold TALVEY until platelet count is 25,000/mcL or higher and no evidence of bleeding. *
Skin Reactions [see Warnings and Precautions (5.7)]	Grade 3–4	Withhold TALVEY until adverse reaction improves to Grade 1 or baseline. *
Other Non-hematologic Adverse Reactions ‡[see Warnings and Precautions (5.8)and Adverse Reactions (6.1)]	Grade 3	Withhold TALVEY until adverse reaction improves to Grade 1 or baseline. *
	Grade 4	Consider permanent discontinuation of TALVEY. If TALVEY is not permanently discontinued, withhold subsequent treatment doses of TALVEY (i.e., doses administered after TALVEY step-up dosing schedule) until adverse reaction improves to Grade 1 or less. *

Preparation and Administration

Administer TALVEY via subcutaneous injection by a healthcare provider.

TALVEY should be administered by a healthcare provider with adequate medical personnel and appropriate medical equipment to manage severe reactions, including CRS and neurologic toxicity, including ICANS [see Warnings and Precautions (5.1, 5.2)] .

TALVEY 3 mg/1.5 mL (2 mg/mL) vial and TALVEY 40 mg/mL vial are supplied as ready-to-use solution for injection that do not need dilution prior to administration.

Do not combine TALVEY vials of different concentrations to achieve treatment dose.

Use aseptic technique to prepare and administer TALVEY.

Preparation

Refer to the following reference tables for the preparation of TALVEY.

Use Table 9 to determine total dose, injection volume, and number of vials required based on patient's actual body weight for the 0.01 mg/kg dose using TALVEY 3 mg/1.5 mL (2 mg/mL) vial.

Table 9: 0.01 mg/kg Dose: Injection Volumes using TALVEY 3 mg/1.5 mL (2 mg/mL) Vial
	Body Weight (kg)	Total Dose (mg)	Volume of Injection (mL)	Number of Vials (1 vial = 1.5 mL)
0.01 mg/kg Dose	35 to 39	0.38	0.19	1
	40 to 45	0.42	0.21	1
	46 to 55	0.5	0.25	1
	56 to 65	0.6	0.3	1
	66 to 75	0.7	0.35	1
	76 to 85	0.8	0.4	1
	86 to 95	0.9	0.45	1
	96 to 105	1	0.5	1
	106 to 115	1.1	0.55	1
	116 to 125	1.2	0.6	1
	126 to 135	1.3	0.65	1
	136 to 145	1.4	0.7	1
	146 to 155	1.5	0.75	1
	156 to 160	1.6	0.8	1

Use Table 10 to determine total dose, injection volume, and number of vials required based on patient's actual body weight for the 0.06 mg/kg dose using TALVEY 3 mg/1.5 mL (2 mg/mL) vial.

Table 10: 0.06 mg/kg Dose: Injection Volumes using TALVEY 3 mg/1.5 mL (2 mg/mL) Vial
	Body Weight (kg)	Total Dose (mg)	Volume of Injection (mL)	Number of Vials (1 vial = 1.5 mL)
0.06 mg/kg Dose	35 to 39	2.2	1.1	1
	40 to 45	2.6	1.3	1
	46 to 55	3	1.5	1
	56 to 65	3.6	1.8	2
	66 to 75	4.2	2.1	2
	76 to 85	4.8	2.4	2
	86 to 95	5.4	2.7	2
	96 to 105	6	3	2
	106 to 115	6.6	3.3	3
	116 to 125	7.2	3.6	3
	126 to 135	7.8	3.9	3
	136 to 145	8.4	4.2	3
	146 to 155	9	4.5	3
	156 to 160	9.6	4.8	4

Use Table 11 to determine total dose, injection volume, and number of vials required based on patient's actual body weight for the 0.4 mg/kg dose using TALVEY 40 mg/mL vial.

Table 11: 0.4 mg/kg Dose: Injection Volumes using TALVEY 40 mg/mL Vial
	Body Weight (kg)	Total Dose (mg)	Volume of Injection (mL)	Number of Vials (1 vial = 1 mL)
0.4 mg/kg Dose	35 to 39	14.8	0.37	1
	40 to 45	16	0.4	1
	46 to 55	20	0.5	1
	56 to 65	24	0.6	1
	66 to 75	28	0.7	1
	76 to 85	32	0.8	1
	86 to 95	36	0.9	1
	96 to 105	40	1	1
	106 to 115	44	1.1	2
	116 to 125	48	1.2	2
	126 to 135	52	1.3	2
	136 to 145	56	1.4	2
	146 to 155	60	1.5	2
	156 to 160	64	1.6	2

Use Table 12 to determine total dose, injection volume, and number of vials required based on patient's actual body weight for the 0.8 mg/kg dose using TALVEY 40 mg/mL vial.

Table 12: 0.8 mg/kg Dose: Injection Volumes using TALVEY 40 mg/mL Vial
	Body Weight (kg)	Total Dose (mg)	Volume of Injection (mL)	Number of Vials (1 vial = 1 mL)
0.8 mg/kg Dose	35 to 39	29.6	0.74	1
	40 to 45	34	0.85	1
	46 to 55	40	1	1
	56 to 65	48	1.2	2
	66 to 75	56	1.4	2
	76 to 85	64	1.6	2
	86 to 95	72	1.8	2
	96 to 105	80	2	2
	106 to 115	88	2.2	3
	116 to 125	96	2.4	3
	126 to 135	104	2.6	3
	136 to 145	112	2.8	3
	146 to 155	120	3	3
	156 to 160	128	3.2	4

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Check that the TALVEY solution for injection is colorless to light yellow. Do not use if the solution is discolored, cloudy, or if foreign particles are present.
Remove the appropriate strength TALVEY vial(s) from refrigerated storage [2°C to 8°C (36°F to 46°F)] and equilibrate to ambient temperature [15°C to 30°C (59°F to 86°F)] for at least 15 minutes. Do not warm TALVEY in any other way.
Once equilibrated, gently swirl the vial for approximately 10 seconds to mix. Do not shake.
Withdraw the required injection volume of TALVEY from the vial(s) into an appropriately sized syringe using a transfer needle.
- Each injection volume should not exceed 2 mL. Divide doses requiring greater than 2 mL equally into multiple syringes.
TALVEY is compatible with stainless steel injection needles and polypropylene or polycarbonate syringe material.
Replace the transfer needle with an appropriately sized needle for injection.

Administration

Inject the required volume of TALVEY into the subcutaneous tissue of the abdomen (preferred injection site). Alternatively, TALVEY may be injected into the subcutaneous tissue at other sites (e.g., thigh). If multiple injections are required, TALVEY injections should be at least 2 cm apart.
Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard or not intact.
Any unused medicinal product or waste material should be disposed in accordance with local requirements.

Storage

The prepared syringes should be administered immediately. If immediate administration is not possible, store the TALVEY solution refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours followed by at room temperature of 15°C to 30°C (59°F to 86°F) for up to 24 hours. Discard if stored for more than 24 hours refrigerated or more than 24 hours at room temperature. If stored in the refrigerator, allow the solution to come to room temperature before administration.