Gammaplex

2.1 Required Laboratory Testing Prior to Initiation and During Therapy

Prior to initiating treatment with clozapine tablets, a baseline ANC must be obtained. The baseline ANC must be at least 1500/μL for the general population, and at least 1000/μL for patients with documented Benign Ethnic Neutropenia (BEN). To continue treatment, the ANC must be monitored regularly [see Warnings and Precautions (5.1)].

2.2 Dosing Information

The starting dose is 12.5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to achieve a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased once weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. To minimize the risk of orthostatic hypotension, bradycardia, and syncope, it is necessary to use this low starting dose, gradual titration schedule, and divided dosages [see Warnings and Precautions (5.3)].

Clozapine tablets can be taken with or without food [see Pharmacokinetics (12.3)].

2.3 Maintenance Treatment

Generally, patients responding to clozapine tablets should continue maintenance treatment on their effective dose beyond the acute episode.

2.4 Discontinuation of Treatment

Method of treatment discontinuation will vary depending on the patient’s last ANC:

• See Tables 2 or 3 for appropriate ANC monitoring based on the level of neutropenia if abrupt treatment discontinuation is necessary because of moderate to severe neutropenia. • Reduce the dose gradually over a period of 1 to 2 weeks if termination of clozapine therapy is planned and there is no evidence of moderate to severe neutropenia. • For abrupt clozapine discontinuation for a reason unrelated to neutropenia, continuation of the existing ANC monitoring is recommended for general population patients until their ANC is ≥ 1500/μL and for BEN patients until their ANC is ≥ 1000/μL or above their baseline. • Additional ANC monitoring is required for any patient reporting onset of fever (temperature of 38.5°C or 101.3°F, or greater) during the 2 weeks after discontinuation [see Warnings and Precautions (5.1)]. • Monitor all patients carefully for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting, and diarrhea. 2.5 Re-Initiation of Treatment

When restarting clozapine tablets in patients who have discontinued clozapine tablets (i.e., 2 days or more since the last dose), re-initiate with 12.5 mg once daily or twice daily. This is necessary to minimize the risk of hypotension, bradycardia, and syncope [see Warnings and Precautions (5.3)]. If that dose is well-tolerated, the dose may be increased to the previously therapeutic dose more quickly than recommended for initial treatment.

2.6 Dosage Adjustments with Concomitant Use of CYP1A2, CYP2D6, CYP3A4 Inhibitors or CYP1A2, CYP3A4 Inducers

Dose adjustments may be necessary in patients with concomitant use of: strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, or enoxacin); moderate or weak CYP1A2 inhibitors (e.g., oral contraceptives, or caffeine); CYP2D6 or CYP3A4 inhibitors (e.g., cimetidine, escitalopram, erythromycin, paroxetine, bupropion, fluoxetine, quinidine, duloxetine, terbinafine, or sertraline); CYP3A4 inducers (e.g., phenytoin, carbamazepine, St. John’s wort, and rifampin); or CYP1A2 inducers (e.g., tobacco smoking) (Table 1) [see Drug Interactions (7)].

Table 1. Dose Adjustment in Patients Taking Concomitant Medications

Co-medications

Scenarios

Initiating clozapine tablets while taking a co-medication

Adding a co-medication while taking clozapine tablets

Discontinuing a co-medication while continuing clozapine tablets

Strong CYP1A2 Inhibitors

Use one-third of the clozapine tablet dose.

Increase clozapine tablet dose based on clinical response.

Moderate or Weak

CYP1A2 Inhibitors

Monitor for adverse reactions. Consider reducing the clozapine tablet dose if necessary.

Monitor for lack of effectiveness. Consider increasing clozapine tablet dose if necessary.

CYP2D6 or CYP3A4 Inhibitors

Strong CYP3A4 Inducers

Concomitant use is not recommended. However, if the inducer is necessary, it may be necessary to increase the clozapine tablet dose. Monitor for decreased effectiveness.

Reduce clozapine tablet dose based on clinical response.

Moderate or weak CYP1A2 or CYP3A4 Inducers

Monitor for decreased effectiveness. Consider increasing the clozapine tablet dose if necessary.

Monitor for adverse reactions. Consider reducing the clozapine tablet dose if necessary.

2.7 Renal or Hepatic Impairment or CYP2D6 Poor Metabolizers

It may be necessary to reduce the clozapine tablet dose in patients with significant renal or hepatic impairment, or in CYP2D6 poor metabolizers [see Use in Specific Populations (8.6, 8.7)].

For Intravenous Use Only

Table 1: Recommended Dosage and Administration for Gammaplex Indication Dose Initial infusion rate Maintenance infusion rate (if tolerated) PI 300-800 mg/kg (6-16 mL/kg) every 3-4 weeks 0.5 mg/kg/min (0.01 mL/kg/min) for 15 min Increase gradually every 15 minutes to 4 mg/kg/min (0.08 mL/kg/min) ITP 1 g/kg (20 mL/kg) for 2 consecutive days 0.5 mg/kg/min (0.01 mL/kg/min) for 15 min Increase gradually every 15 minutes to 4 mg/kg/min (0.08 mL/kg/min) 2.1 Preparation and Handling Gammaplex is a clear or slightly opalescent, colorless solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the solution is cloudy or turbid, or if it contains particulate matter. Do not freeze, and do not use any solution that has been frozen. DO NOT SHAKE. Gammaplex should be at room temperature (up to 25°C [77°F]) at the time of administration. Do not use Gammaplex beyond the expiration date on the product label. The Gammaplex vial is for single use only. Due to the absence of anti-microbial preservatives, promptly administer Gammaplex after piercing the cap. Dispose of partially used or unused product. Infuse Gammaplex using a separate infusion line. Do not mix Gammaplex with other intravenous medications (including normal saline) or other IGIV products. An infusion pump may be used to control the rate of administration. If large doses of Gammaplex are to be administered, several vials may be pooled using aseptic technique. Begin infusion within 2 hours after pooling. 2.2 Recommended Dose

Treatment of Primary Humoral Immunodeficiency

As there are significant differences in the half-life of IgG among patients with PI, the frequency and amount of immunoglobulin therapy may vary from patient to patient. The proper amount can be determined by monitoring clinical response.

The recommended dose of Gammaplex for patients with PI is 300 to 800 mg/kg (6 to 16 mL/kg), administered every 3 to 4 weeks. Adjust the dosage over time to achieve the desired serum trough levels and clinical response. If a patient misses a dose, administer the missed dose as soon as possible, and then resume scheduled treatments every 3 or 4 weeks, as applicable.

Treatment of Chronic Immune Thrombocytopenic Purpura

The recommended dose of Gammaplex for patients with ITP is 1 g/kg (20 mL/kg) on 2 consecutive days, providing a total dose of 2 g/kg. Carefully consider the relative risks and benefits before prescribing the high dose regimen (i.e. 1 g/kg/day for 2 days) in patients at increased risk of thrombosis, hemolysis, acute kidney injury, or volume overload [see Warnings and Precautions (5)]. Adequate data on the platelet response to the low dose regimen (e.g. 400 mg/kg per day for 5 consecutive days) are not available for Gammaplex.

2.3 Administration Hydrate the patient adequately prior to the initiation of infusion. Due to the absence of anti-microbial preservatives, promptly administer Gammaplex after piercing the cap. Infuse Gammaplex intravenously using an intravenous infusion set. See Table 1 for recommended infusion rates. Monitor vital signs throughout the infusion. Slow or stop the infusion if adverse reactions occur. If symptoms subside, the infusion may be resumed at a lower rate that is comfortable for the patient. The observation time of patients after Gammaplex administration may vary. If the patient (a) has not received Gammaplex or another IgG product, (b) is switched from an alternative IGIV product or (c) has had a long interval since the previous infusion, prolong the observation time for adverse reactions after Gammaplex infusion. Certain severe adverse reactions may be related to the rate of infusion. Slowing or stopping the infusion often allows the reaction to disappear. Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients at increased risk of renal dysfunction, thrombotic events, or volume overload, administer Gammaplex at the minimum infusion rate practicable. Consider discontinuing Gammaplex administration if renal function deteriorates [see Boxed Warning, Warnings and Precautions (5.1, 5.2, 5.8)].