DOSAGE AND ADMINISTRATION

2 Administer once daily, on an empty stomach, one-half to one hour before breakfast with a full glass of water.

( 2.1 ) Administer at least 4 hours before or after drugs that are known to interfere with absorption ( 2.1 ) Evaluate the need for dose adjustments when regularly administering within one hour of certain foods that may affect absorption.

( 2.1 ) Starting dose depends on a variety of factors, including age, body weight, cardiovascular status, concomitant medical conditions (including pregnancy), concomitant medications, co-administered food, and the specific nature of the condition being treated.

Peak therapeutic effect may not be attained for 4 to 6 weeks.

( 2.2 ) See full prescribing information for dosing in specific patient populations.

( 2.3 ) Adequacy of therapy determined with periodic monitoring of TSH and/or T4 as well as clinical status.

( 2.4 ) 2.1 General Administration Information Administer UNITHROID tablets orally as a single daily dose, on an empty stomach, one-half to one hour before breakfast.

Administer UNITHROID at least 4 hours before or after drugs that are known to interfere with UNITHROID absorption [see Drug Interactions ( 7.1 )] .

Evaluate the need for dose adjustments when regularly administering within one hour of certain foods that may affect UNITHROID absorption [see Drug Interactions ( 7.9 ), Clinical Pharmacology ( 12.3 )] .

Administer UNITHROID to infants and children who cannot swallow intact tablets by crushing the tablet, suspending the freshly crushed tablet in a small amount (5 mL to 10 mL or 1 teaspoon to 2 teaspoons) of water and immediately administering the suspension by spoon or dropper.

Do not store the suspension.

Do not administer in foods that decrease absorption of UNITHROID, such as soybean-based infant formula [see Drug Interactions ( 7.9 )] .

2.2 General Principles of Dosing The dose of UNITHROID for hypothyroidism or pituitary TSH suppression depends on a variety of factors including: the patient’s age, body weight, cardiovascular status, concomitant medical conditions (including pregnancy), concomitant medications, co-administered food and the specific nature of the condition being treated [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5 ), Drug Interactions ( 7 )] .

Dosing must be individualized to account for these factors and dose adjustments made based on periodic assessment of the patient’s clinical response and laboratory parameters [see Dosage and Administration ( 2.4 )] .

The peak therapeutic effect of a given dose of UNITHROID may not be attained for 4 to 6 weeks.

2.3 Dosing in Specific Populations Primary Hypothyroidism in Adults and in Adolescents in Whom Growth and Puberty Are Complete Start UNITHROID at the full replacement dose in otherwise healthy, non-elderly individuals who have been hypothyroid for only a short time (such as a few months).

The average full replacement dose of UNITHROID is approximately 1.6 mcg per kg per day (for example: 100 mcg per day to 125 mcg per day for a 70 kg adult).

Adjust the dose by 12.5 mcg to 25 mcg increments every 4 to 6 weeks until the patient is clinically euthyroid and the serum TSH returns to normal.

Doses greater than 200 mcg per day are seldom required.

An inadequate response to daily doses of greater than 300 mcg per day is rare and may indicate poor compliance, malabsorption, drug interactions, or a combination of these factors.

For elderly patients or patients with underlying cardiac disease, start with a dose of 12.5 mcg to 25 mcg per day.

Increase the dose every 6 to 8 weeks, as needed until the patient is clinically euthyroid and the serum TSH returns to normal.

The full replacement dose of UNITHROID may be less than 1 mcg per kg per day in elderly patients.

In patients with severe longstanding hypothyroidism, start with a dose of 12.5 mcg to 25 mcg per day.

Adjust the dose in 12.5 mcg to 25 mcg increments every 2 to 4 weeks until the patient is clinically euthyroid and the serum TSH level is normalized.

Secondary or Tertiary Hypothyroidism Start UNITHROID at the full replacement dose in otherwise healthy, non-elderly individuals.

Start with a lower dose in elderly patients, patients with underlying cardiovascular disease or patients with severe longstanding hypothyroidism as described above.

Serum TSH is not a reliable measure of UNITHROID dose adequacy in patients with secondary or tertiary hypothyroidism and should not be used to monitor therapy.

Use the serum free-T4 level to monitor adequacy of therapy in this patient population.

Titrate UNITHROID dosing per above instructions until the patient is clinically euthyroid and the serum free-T4 level is restored to the upper half of the normal range.

Pediatric Dosage – Congenital or Acquired Hypothyroidism The recommended daily dose of UNITHROID in pediatric patients with hypothyroidism is based on body weight and changes with age as described in Table 1.

Start UNITHROID at the full daily dose in most pediatric patients.

Start at a lower starting dose in newborns (0 to 3 months) at risk for cardiac failure and in children at risk for hyperactivity (see below).

Monitor for clinical and laboratory response [see Dosage and Administration ( 2.4 )] .

Table 1: UNITHROID Dosing Guidelines for Pediatric Hypothyroidism Age Daily Dose Per Kg Body Weight a 0 to 3 months 10 mcg/kg daily to 15 mcg/kg daily 3 to 6 months 8 mcg/kg daily to 10 mcg/kg daily 6 to 12 months 6 mcg/kg daily to 8 mcg/kg daily 1 to 5 years 5 mcg/kg to 6 mcg/kg daily 6 to 12 years 4 mcg/kg to 5 mcg/kg daily Greater than 12 years but growth and puberty incomplete 2 mcg/kg to 3 mcg/kg daily Growth and puberty complete 1.6 mcg/kg daily a – The dose should be adjusted based on clinical response and laboratory parameters [see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7.10 ), and Use In Specific Populations ( 8.4 )] .

Newborns (0 to 3 months) at Risk for Cardiac Failure: Consider a lower starting dose in newborns at risk for cardiac failure.

Increase the dose every 4 to 6 weeks as needed based on clinical and laboratory response.

Pediatric Patients at Risk for Hyperactivity: To minimize the risk of hyperactivity in pediatric patients, start at one-fourth the recommended full replacement dose, and increase on a weekly basis by one-fourth the full recommended replacement dose until the full recommended replacement dose is reached.

Pregnancy Pre-existing Hypothyroidism: UNITHROID dose requirements may increase during pregnancy.

Measure serum TSH and free-T4 as soon as pregnancy is confirmed and, at minimum, during each trimester of pregnancy.

In patients with primary hypothyroidism, maintain serum TSH in the trimester-specific reference range.

For patients with serum TSH above the normal trimester-specific range, increase the dose of UNITHROID by 12.5 mcg daily to 25 mcg daily and measure TSH every 4 weeks until a stable UNITHROID dose is reached and serum TSH is within the normal trimester-specific range.

Reduce UNITHROID dosage to pre-pregnancy levels immediately after delivery and measure serum TSH levels 4 to 8 weeks postpartum to ensure UNITHROID dose is appropriate.

New Onset Hypothyroidism: Normalize thyroid function as rapidly as possible.

In patients with moderate to severe signs and symptoms of hypothyroidism, start UNITHROID at the full replacement dose (1.6 mcg per kg body weight per day).

In patients with mild hypothyroidism (TSH less than 10 mIU per liter) start UNITHROID at 1 mcg per kg body weight per day.

Evaluate serum TSH every 4 weeks and adjust UNITHROID dosage until a serum TSH is within the normal trimester specific range [see Use in Specific Populations ( 8.1 )] .

TSH Suppression in Well-Differentiated Thyroid Cancer The dose of UNITHROID should target TSH levels within the desired therapeutic range.

This may require a UNITHROID dose of greater than 2 mcg per kg per day, depending on the target level for TSH suppression.

2.4 Monitoring TSH and/or Thyroxine (T4) Levels Assess the adequacy of therapy by periodic assessment of laboratory tests and clinical evaluation.

Persistent clinical and laboratory evidence of hypothyroidism despite an apparent adequate replacement dose of UNITHROID may be evidence of inadequate absorption, poor compliance, drug interactions, or a combination of these factors.

Adults In adult patients with primary hypothyroidism, monitor serum TSH levels after an interval of 6 to 8 weeks after any change in dose.

In patients on a stable and appropriate replacement dose, evaluate clinical and biochemical response every 6 to 12 months and whenever there is a change in the patient’s clinical status.

Pediatrics In patients with congenital hypothyroidism, assess the adequacy of replacement therapy by measuring both serum TSH and total or free-T.

Monitor TSH and total or free-T4 in children as follows: 2 and 4 weeks after the initiation of treatment, 2 weeks after any change in dosage, and then every 3 to 12 months thereafter following dose stabilization until growth is completed.

Poor compliance or abnormal values may necessitate more frequent monitoring.

Perform routine clinical examination, including assessment of development, mental and physical growth, and bone maturation, at regular intervals.

While the general aim of therapy is to normalize the serum TSH level, TSH may not normalize in some patients due to in utero hypothyroidism causing a resetting of pituitary-thyroid feedback.

Failure of the serum T4 to increase into the upper half of the normal range within 2 weeks of initiation of UNITHROID therapy and/or of the serum TSH to decrease below 20 mIU per liter within 4 weeks may indicate the child is not receiving adequate therapy.

Assess compliance, dose of medication administered, and method of administration prior to increasing the dose of UNITHROID [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.4 )] )].

Secondary and Tertiary Hypothyroidism Monitor serum free-T4 levels and maintain in the upper half of the normal range in these patients.

DOSAGE AND ADMINISTRATION

2 Starting dose: 150 mg/day ( 2.1 ) General: Increase dose gradually to reduce seizure risk.

( 2.1 , 5.3 ) After 3 days, may increase the dose to 300 mg/day, given as 150 mg twice daily at an interval of at least 8 hours.

( 2.1 ) Usual target dose: 300 mg/day as 150 mg twice daily.

( 2.1 ) Maximum dose: 400 mg/day, given as 200 mg twice daily, for patients not responding to 300 mg/day.

(2.1) Periodically reassess the dose and need for maintenance treatment.

( 2.1 ) Moderate to severe hepatic impairment: 100 mg daily or 150 mg every other day.

( 2.2 , 8.7 ) Mild hepatic impairment: Consider reducing the dose and/or frequency of dosing.

( 2.2 , 8.7 ) Renal impairment: Consider reducing the dose and/or frequency.

( 2.3 , 8.6 ) 2.1 General Instructions for Use To minimize the risk of seizure, increase the dose gradually [see Warnings and Precautions ( 5.3 )] .

Bupropion hydrochloride extended-release tablets (SR) should be swallowed whole and not crushed, divided, or chewed.

Bupropion hydrochloride extended-release tablets (SR) may be taken with or without food.

The usual adult target dose for bupropion hydrochloride extended-release tablets (SR) is 300 mg/day, given as 150 mg twice daily.

Initiate dosing with 150 mg/day given as a single daily dose in the morning.

After 3 days of dosing, the dose may be increased to the 300-mg/day target dose, given as 150 mg twice daily.

There should be an interval of at least 8 hours between successive doses.

A maximum of 400 mg/day, given as 200 mg twice daily, may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 300 mg/day.

To avoid high peak concentrations of bupropion and/or its metabolites, do not exceed 200 mg in any single dose.

It is generally agreed that acute episodes of depression require several months or longer of antidepressant drug treatment beyond the response in the acute episode.

It is unknown whether the dose of bupropion hydrochloride extended-release tablets (SR) needed for maintenance treatment is identical to the dose that provided an initial response.

Periodically reassess the need for maintenance treatment and the appropriate dose for such treatment.

2.2 Dose Adjustment in Patients with Hepatic Impairment In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of bupropion hydrochloride extended-release tablets (SR) is 100 mg/day or 150 mg every other day.

In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )].

2.3 Dose Adjustment in Patients with Renal Impairment Consider reducing the dose and/or frequency of bupropion hydrochloride extended-release tablets (SR) in patients with renal impairment (Glomerular Filtration Rate less than 90 mL/min) [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )] .

2.4 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with bupropion hydrochloride extended-release tablets (SR).

Conversely, at least 14 days should be allowed after stopping bupropion hydrochloride extended-release tablets (SR) before starting an MAOI antidepressant [see Contraindications ( 4 ), Drug Interactions ( 7.6 )] .

2.5 Use of Bupropion Hydrochloride Extended-release Tablets (SR) with Reversible MAOIs Such as Linezolid or Methylene Blue Do not start bupropion hydrochloride extended-release tablets (SR) in a patient who is being treated with a reversible MAOI such as linezolid or intravenous methylene blue.

Drug interactions can increase the risk of hypertensive reactions.

In a patient who requires more urgent treatment of a psychiatric condition, non-pharmacological interventions, including hospitalization, should be considered [see Contraindications ( 4 ), Drug Interactions ( 7.6 )] .

In some cases, a patient already receiving therapy with bupropion hydrochloride extended-release tablets (SR) may require urgent treatment with linezolid or intravenous methylene blue.

If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of hypertensive reactions in a particular patient, bupropion hydrochloride extended-release tablets (SR) should be stopped promptly, and linezolid or intravenous methylene blue can be administered.

The patient should be monitored for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first.

Therapy with bupropion hydrochloride extended-release tablets (SR) may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with bupropion hydrochloride extended-release tablets (SR) is unclear.

The clinician should, nevertheless, be aware of the possibility of a drug interaction with such use [see Contraindications ( 4 ), Drug Interactions ( 7.6 )] .

DOSAGE AND ADMINISTRATION

Directions • adults and children 6 to under 12 years of age (with adult supervision): 2 or 3 sprays in each nostril not more often than every 10 to 12 hours.

Do not exceed 2 doses in any 24-hour period.

• children under 6 years of age: ask a doctor To spray, squeeze bottle quickly and firmly.

Do not tilt head backward while spraying.

Wipe nozzle clean after use.

DOSAGE AND ADMINISTRATION

2 For subcutaneous or intravenous use only.

Each route of administration has a different reconstituted concentration.

Exercise caution when calculating the volume to be administered.

( 2.1 , 2.10 ) The recommended starting dose of VELCADE is 1.3 mg/m 2 administered either as a 3 to 5 second bolus intravenous injection or subcutaneous injection.

( 2.2 , 2.4 , 2.6 ) Retreatment for Multiple Myeloma: May retreat starting at the last tolerated dose.

( 2.6 ) Hepatic Impairment: Use a lower starting dose for patients with moderate or severe hepatic impairment.

( 2.8 ) Dose must be individualized to prevent overdose.

( 2.10 ) 2.1 Important Dosing Guidelines VELCADE is for intravenous or subcutaneous use only.

Do not administer VELCADE by any other route.

Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered.

The recommended starting dose of VELCADE is 1.3 mg/m 2 .

VELCADE is administered intravenously at a concentration of 1 mg/mL, or subcutaneously at a concentration of 2.5 mg/mL [see Dosage and Administration (2.10) ] .

VELCADE retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with VELCADE and who have relapsed at least six months after completing prior VELCADE treatment.

Treatment may be started at the last tolerated dose [see Dosage and Administration (2.6) ] .

When administered intravenously, administer VELCADE as a 3 to 5 second bolus intravenous injection.

2.2 Dosage in Previously Untreated Multiple Myeloma VELCADE is administered in combination with oral melphalan and oral prednisone for 9, six week treatment cycles as shown in Table 1 .

In Cycles 1 to 4, VELCADE is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29 and 32).

In Cycles 5 to 9, VELCADE is administered once weekly (Days 1, 8, 22 and 29).

At least 72 hours should elapse between consecutive doses of VELCADE.

Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma Twice Weekly VELCADE (Cycles 1 to 4) Week 1 2 3 4 5 6 VELCADE (1.3 mg/m 2 ) Day 1 — — Day 4 Day 8 Day 11 rest period Day 22 Day 25 Day 29 Day 32 rest period Melphalan (9 mg/m 2 ) Prednisone (60 mg/m 2 ) Day 1 Day 2 Day 3 Day 4 — — rest period — — — — rest period Once Weekly VELCADE (Cycles 5 to 9 when used in combination with Melphalan and Prednisone) Week 1 2 3 4 5 6 VELCADE (1.3 mg/m 2 ) Day 1 — — Day 8 rest period Day 22 Day 29 rest period Melphalan (9 mg/m 2 ) Prednisone (60 mg/m 2 ) Day 1 Day 2 Day 3 Day 4 — — rest period — — — — rest period 2.3 Dose Modification Guidelines for VELCADE When Given in Combination with Melphalan and Prednisone Prior to initiating any cycle of therapy with VELCADE in combination with melphalan and prednisone: Platelet count should be at least 70 × 10 9 /L and the absolute neutrophil count (ANC) should be at least 1 × 10 9 /L Nonhematological toxicities should have resolved to Grade 1 or baseline Table 2: Dose Modifications During Cycles of Combination VELCADE, Melphalan and Prednisone Therapy Toxicity Dose Modification or Delay Hematological toxicity during a cycle: If prolonged Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle Consider reduction of the melphalan dose by 25% in the next cycle If platelet count is not above 30 × 10 9 /L or ANC is not above 0.75 × 10 9 /L on a VELCADE dosing day (other than Day 1) Withhold VELCADE dose If several VELCADE doses in consecutive cycles are withheld due to toxicity Reduce VELCADE dose by one dose level (from 1.3 mg/m 2 to 1 mg/m 2 , or from 1 mg/m 2 to 0.7 mg/m 2 ) Grade 3 or higher nonhematological toxicities Withhold VELCADE therapy until symptoms of toxicity have resolved to Grade 1 or baseline.

Then, VELCADE may be reinitiated with one dose level reduction (from 1.3 mg/m 2 to 1 mg/m 2 , or from 1 mg/m 2 to 0.7 mg/m 2 ).

For VELCADE-related neuropathic pain and/or peripheral neuropathy, hold or modify VELCADE as outlined in Table 5 .

For information concerning melphalan and prednisone, see manufacturer’s prescribing information.

Dose modifications guidelines for peripheral neuropathy are provided [see Dosage and Administration (2.7) ] .

2.4 Dosage in Previously Untreated Mantle Cell Lymphoma VELCADE (1.3 mg/m 2 ) is administered intravenously in combination with intravenous rituximab, cyclophosphamide, doxorubicin and oral prednisone (VcR-CAP) for 6, three week treatment cycles as shown in Table 3 .

VELCADE is administered first followed by rituximab.

VELCADE is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a ten day rest period on Days 12 to 21.

For patients with a response first documented at Cycle 6, two additional VcR-CAP cycles are recommended.

At least 72 hours should elapse between consecutive doses of VELCADE.

Table 3: Dosage Regimen for Patients with Previously Untreated Mantle Cell Lymphoma Twice Weekly VELCADE (6, Three Week Cycles) Dosing may continue for two more cycles (for a total of eight cycles) if response is first seen at Cycle 6.

Week 1 2 3 VELCADE (1.3 mg/m 2 ) Day 1 — — Day 4 — Day 8 Day 11 rest period Rituximab (375 mg/m 2 ) Cyclophosphamide (750 mg/m 2 ) Doxorubicin (50 mg/m 2 ) Day 1 — — — — rest period Prednisone (100 mg/m 2 ) Day 1 Day 2 Day 3 Day 4 Day 5 — — rest period 2.5 Dose Modification Guidelines for VELCADE When Given in Combination with Rituximab, Cyclophosphamide, Doxorubicin and Prednisone Prior to the first day of each cycle (other than Cycle 1): Platelet count should be at least 100 × 10 9 /L and absolute neutrophil count (ANC) should be at least 1.5 × 10 9 /L Hemoglobin should be at least 8 g/dL (at least 4.96 mmol/L) Nonhematologic toxicity should have recovered to Grade 1 or baseline Interrupt VELCADE treatment at the onset of any Grade 3 hematologic or nonhematological toxicities, excluding neuropathy [see Table 5, Warnings and Precautions (5) ] .

For dose adjustments, see Table 4 below.

Table 4: Dose Modifications on Days 4, 8, and 11 During Cycles of Combination VELCADE, Rituximab, Cyclophosphamide, Doxorubicin and Prednisone Therapy Toxicity Dose Modification or Delay Hematological Toxicity Grade 3 or higher neutropenia, or a platelet count not at or above 25 × 10 9 /L Withhold VELCADE therapy for up to 2 weeks until the patient has an ANC at or above 0.75 × 10 9 /L and a platelet count at or above 25 × 10 9 /L.

If, after VELCADE has been withheld, the toxicity does not resolve, discontinue VELCADE.

If toxicity resolves such that the patient has an ANC at or above 0.75 × 10 9 /L and a platelet count at or above 25 × 10 9 /L, VELCADE dose should be reduced by 1 dose level (from 1.3 mg/m 2 to 1 mg/m 2 , or from 1 mg/m 2 to 0.7 mg/m 2 ).

Grade 3 or higher nonhematological toxicities Withhold VELCADE therapy until symptoms of the toxicity have resolved to Grade 2 or better.

Then, VELCADE may be reinitiated with one dose level reduction (from 1.3 mg/m 2 to 1 mg/m 2 , or from 1 mg/m 2 to 0.7 mg/m 2 ).

For VELCADE-related neuropathic pain and/or peripheral neuropathy, hold or modify VELCADE as outlined in Table 5 .

For information concerning rituximab, cyclophosphamide, doxorubicin and prednisone, see manufacturer’s prescribing information.

2.6 Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma VELCADE (1.3 mg/m 2 /dose) is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a ten day rest period (Days 12 to 21).

For extended therapy of more than eight cycles, VELCADE may be administered on the standard schedule or, for relapsed multiple myeloma, on a maintenance schedule of once weekly for four weeks (Days 1, 8, 15, and 22) followed by a 13 day rest period (Days 23 to 35) [see Clinical Studies (14) ] .

At least 72 hours should elapse between consecutive doses of VELCADE.

Patients with multiple myeloma who have previously responded to treatment with VELCADE (either alone or in combination) and who have relapsed at least six months after their prior VELCADE therapy may be started on VELCADE at the last tolerated dose.

Retreated patients are administered VELCADE twice weekly (Days 1, 4, 8, and 11) every three weeks for a maximum of eight cycles.

At least 72 hours should elapse between consecutive doses of VELCADE.

VELCADE may be administered either as a single agent or in combination with dexamethasone [see Clinical Studies (14.1) ] .

VELCADE therapy should be withheld at the onset of any Grade 3 nonhematological or Grade 4 hematological toxicities excluding neuropathy as discussed below [see Warnings and Precautions (5) ] .

Once the symptoms of the toxicity have resolved, VELCADE therapy may be reinitiated at a 25% reduced dose (1.3 mg/m 2 /dose reduced to 1 mg/m 2 /dose; 1 mg/m 2 /dose reduced to 0.7 mg/m 2 /dose).

For dose modifications guidelines for peripheral neuropathy, see section 2.7 .

2.7 Dose Modifications for Peripheral Neuropathy Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule.

For dose or schedule modification guidelines for patients who experience VELCADE-related neuropathic pain and/or peripheral neuropathy, see Table 5 .

Table 5: Recommended Dose Modification for VELCADE-Related Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy Severity of Peripheral Neuropathy Signs and Symptoms Grading based on NCI Common Terminology Criteria CTCAE v4.0 Modification of Dose and Regimen Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or loss of function No action Grade 1 with pain or Grade 2 (moderate symptoms; limiting instrumental Activities of Daily Living (ADL) Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money, etc.

) Reduce VELCADE to 1 mg/m 2 Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADL Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden ) Withhold VELCADE therapy until toxicity resolves.

When toxicity resolves reinitiate with a reduced dose of VELCADE at 0.7 mg/m 2 once per week.

Grade 4 (life-threatening consequences; urgent intervention indicated) Discontinue VELCADE 2.8 Dosage in Patients with Hepatic Impairment Do not adjust the starting dose for patients with mild hepatic impairment.

Start patients with moderate or severe hepatic impairment at a reduced dose of 0.7 mg/m 2 per injection during the first cycle, and consider subsequent dose escalation to 1 mg/m 2 or further dose reduction to 0.5 mg/m 2 based on patient tolerance (see Table 6 ) [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ] .

Table 6: Recommended Starting Dose Modification for VELCADE in Patients with Hepatic Impairment Bilirubin Level SGOT (AST) Levels Modification of Starting Dose Abbreviations: SGOT = serum glutamic oxaloacetic transaminase; AST = aspartate aminotransferase; ULN = upper limit of the normal range.

Mild Less than or equal to 1× ULN More than ULN None More than 1× to 1.5× ULN Any None Moderate More than 1.5× to 3× ULN Any Reduce VELCADE to 0.7 mg/m 2 in the first cycle.

Consider dose escalation to 1 mg/m 2 or further dose reduction to 0.5 mg/m 2 in subsequent cycles based on patient tolerability.

Severe More than 3× ULN Any 2.9 Administration Precautions The drug quantity contained in one vial (3.5 mg) may exceed the usual dose required.

Caution should be used in calculating the dose to prevent overdose [see Dosage and Administration (2.10) ] .

When administered subcutaneously, sites for each injection (thigh or abdomen) should be rotated.

New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated.

If local injection site reactions occur following VELCADE administration subcutaneously, a less concentrated VELCADE solution (1 mg/mL instead of 2.5 mg/mL) may be administered subcutaneously [see Dosage and Administration (2.10) ] .

Alternatively, consider use of the intravenous route of administration [see Dosage and Administration (2.10) ] .

VELCADE is a hazardous drug.

Follow applicable special handling and disposal procedures.

1 2.10 Reconstitution/Preparation for Intravenous and Subcutaneous Administration Use proper aseptic technique.

Reconstitute only with 0.9% sodium chloride .

The reconstituted product should be a clear and colorless solution.

Different volumes of 0.9% sodium chloride are used to reconstitute the product for the different routes of administration.

The reconstituted concentration of bortezomib for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration of bortezomib for intravenous administration (1 mg/mL).

Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered [see Dosage and Administration (2.9) ] .

For each 3.5 mg single-dose vial of bortezomib, reconstitute with the following volume of 0.9% sodium chloride based on route of administration (Table 7) : Table 7: Reconstitution Volumes and Final Concentration for Intravenous and Subcutaneous Administration Route of Administration Bortezomib (mg/vial) Diluent (0.9% Sodium Chloride) Final Bortezomib Concentration (mg/mL) Intravenous 3.5 mg 3.5 mL 1 mg/mL Subcutaneous 3.5 mg 1.4 mL 2.5 mg/mL Dose must be individualized to prevent overdosage.

After determining patient body surface area (BSA) in square meters, use the following equations to calculate the total volume (mL) of reconstituted VELCADE to be administered: Intravenous Administration [1 mg/mL concentration] VELCADE dose (mg/m 2 ) × patient BSA (m 2 ) =Total VELCADE volume (mL) to be administered 1 mg/mL Subcutaneous Administration [2.5 mg/mL concentration] VELCADE dose (mg/m 2 ) × patient BSA (m 2 ) =Total VELCADE volume (mL) to be administered 2.5 mg/mL Stickers that indicate the route of administration are provided with each VELCADE vial.

These stickers should be placed directly on the syringe of VELCADE once VELCADE is prepared to help alert practitioners of the correct route of administration for VELCADE.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

If any discoloration or particulate matter is observed, the reconstituted product should not be used.

Stability Unopened vials of VELCADE are stable until the date indicated on the package when stored in the original package protected from light.

VELCADE contains no antimicrobial preservative.

Administer reconstituted VELCADE within eight hours of preparation.

When reconstituted as directed, VELCADE may be stored at 25°C (77°F).

The reconstituted material may be stored in the original vial and/or the syringe prior to administration.

The product may be stored for up to eight hours in a syringe; however, total storage time for the reconstituted material must not exceed eight hours when exposed to normal indoor lighting.

DOSAGE AND ADMINISTRATION

2 During or immediately after the administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urinary tract toxicity.

Therefore, cyclophosphamide should be administered in the morning.

Malignant Diseases: Adult and Pediatric Patients ( 2.1 ) Intravenous: Initial course for patients with no hematologic deficiency: 40 mg per kg to 50 mg per kg in divided doses over 2 to 5 days.

Other regimens include 10 mg per kg to 15 mg per kg given every 7 to 10 days or 3 mg per kg to 5 mg per kg twice weekly.

Oral: Usually 1 mg per kg per day to 5 mg per kg per day for both initial and maintenance dosing.

Minimal Change Nephrotic Syndrome in Pediatric Patients ( 2.2 ) Recommended oral dose: 2 mg per kg daily for 8 to 12 weeks (maximum cumulative dose 168 mg per kg).

Treatment beyond 90 days increases the probability of sterility in males.

2.1 Dosing for Malignant Diseases Adults and Pediatric Patients Intravenous When used as the only oncolytic drug therapy, the initial course of cyclophosphamide for patients with no hematologic deficiency usually consists of 40 mg per kg to 50 mg per kg given intravenously in divided doses over a period of 2 to 5 days.

Other intravenous regimens include 10 mg per kg to 15 mg per kg given every 7 to 10 days or 3 mg per kg to 5 mg per kg twice weekly.

Oral Oral cyclophosphamide dosing is usually in the range of 1 mg per kg per day to 5 mg per kg per day for both initial and maintenance dosing.

Many other regimens of intravenous and oral cyclophosphamide have been reported.

Dosages must be adjusted in accord with evidence of antitumor activity and/ or leukopenia.

The total leukocyte count is a good, objective guide for regulating dosage.

When cyclophosphamide is included in combined cytotoxic regimens, it may be necessary to reduce the dose of cyclophosphamide as well as that of the other drugs.

2.2 Dosing for Minimal Change Nephrotic Syndrome in Pediatric Patients An oral dose of 2 mg per kg daily for 8 to 12 weeks (maximum cumulative dose 168 mg per kg) is recommended.

Treatment beyond 90 days increases the probability of sterility in males [see Use in Specific Populations ( 8.4 )].

2.3 Preparation, Handling and Administration Handle and dispose of cyclophosphamide in a manner consistent with other cytotoxic drugs.

1 Caution should be exercised when handling and preparing Cyclophosphamide for Injection, USP.

To minimize the risk of dermal exposure, always wear gloves when handling vials containing Cyclophosphamide for Injection, USP.

Cyclophosphamide for Injection, USP Intravenous Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Do not use cyclophosphamide vials if there are signs of melting.

Melted cyclophosphamide is a clear or yellowish viscous liquid usually found as a connected phase or in droplets in the affected vials.

Cyclophosphamide does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions.

Use aseptic technique.

For Direct Intravenous Injection Reconstitute Cyclophosphamide with 0.9% Sodium Chloride Injection, USP only, using the volumes listed below in Table 1.

Shake the vial vigorously to dissolve the drug completely.

Do not use Sterile Water for Injection, USP because it results in a hypotonic solution and should not be injected directly.

Table 1: Reconstitution for Direct Intravenous Injection Strength Volume of 0.9% Sodium Chloride Cyclophosphamide Concentration 500 mg 25 mL 20 mg per mL 1 g 50 mL 2 g 100 mL For Intravenous Infusion Reconstitution of Cyclophosphamide: Reconstitute Cyclophosphamide using 0.9% Sodium Chloride Injection, USP or Sterile Water for Injection, USP with the volume of diluent listed below in Table 2.

Add the diluent to the vial and shake it vigorously to dissolve the drug completely.

Table 2: Reconstitution in preparation for Intravenous Infusion Strength Volume of Diluent Cyclophosphamide Concentration 500 mg 25 mL 20 mg per mL 1 g 50 mL 2 g 100 mL Dilution of Reconstituted Cyclophosphamide: Further dilute the reconstituted Cyclophosphamide solution to a minimum concentration of 2 mg per mL with any of the following diluents: 5% Dextrose Injection, USP 5% Dextrose and 0.9% Sodium Chloride Injection, USP 0.45% Sodium Chloride Injection, USP To reduce the likelihood of adverse reactions that appear to be administration rate-dependent (e.g., facial swelling, headache, nasal congestion, scalp burning), cyclophosphamide should be injected or infused very slowly.

Duration of the infusion also should be appropriate for the volume and type of carrier fluid to be infused.

Storage of Reconstituted and Diluted Cyclophosphamide Solution: If not used immediately, for microbiological integrity, cyclophosphamide solutions should be stored as described in Table 3.

Table 3: Storage of Cyclophosphamide Solutions Diluent Storage Room Temperature Refrigerated Reconstituted Solution (Without Further Dilution) 0.9% Sodium Chloride Injection, USP up to 24 hrs up to 6 days Sterile Water for Injection, USP Do not store; use immediately Diluted Solutions Storage time is the total time cyclophosphamide is in solution including the time it is reconstituted in 0.9% Sterile Sodium Chloride Injection, USP or Sterile Water for Injection, USP.

0.45% Sodium Chloride Injection, USP up to 24 hrs up to 6 days 5% Dextrose Injection, USP up to 24 hrs up to 36 hrs 5% Dextrose and 0.9% Sodium Chloride Injection, USP up to 24 hrs up to 36 hrs Use of Reconstituted Solution for Oral Administration Liquid preparations of cyclophosphamide for oral administration may be prepared by dissolving cyclophosphamide for injection in Aromatic Elixir, National Formulary (NF).

Such preparations should be stored under refrigeration in glass containers and used within 14 days.

DOSAGE AND ADMINISTRATION

The adhesive side of Vivelle-Dot ® (estradiol transdermal system) should be placed on a clean, dry area of the abdomen.

Vivelle -Dot should not be applied to the breasts.

Vivelle-Dot should be replaced twice weekly.

The sites of application must be rotated, with an interval of at least 1 week allowed between applications to a particular site.

The area selected should not be oily, damaged, or irritated.

The waistline should be avoided, since tight clothing may rub the system off.

The system should be applied immediately after opening the pouch and removing the protective liner.

The system should be pressed firmly in place with the palm of the hand for about 10 seconds, making sure there is good contact, especially around the edges.

In the event that a system should fall off, the same system may be reapplied.

If the same system cannot be reapplied, a new system should be applied to another location.

In either case, the original treatment schedule should be continued.

If a woman has forgotten to apply a patch, she should apply a new patch as soon as possible.

The new patch should be applied on the original treatment schedule.

The interruption of treatment in women taking Vivelle-Dot might increase the likelihood of breakthrough bleeding, spotting and recurrence of symptoms.

Initiation of Therapy When estrogen is prescribed for a postmenopausal woman with a uterus, progestin should also be initiated to reduce the risk of endometrial cancer.

A woman without a uterus does not need progestin.

Use of estrogen alone or in combination with a progestin, should be with the lowest effective dose and the shortest duration consistent with treatment goals and risks for the individual woman.

Patients should be reevaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine whether treatment is still necessary (see BOXED WARNINGS and WARNINGS ).

For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.

Patients should be started at the lowest dose.

The lowest effective dose of Vivelle-Dot has not been determined for any indication.

For treatment of moderate to severe vasomotor symptoms and vulvar and vaginal atrophy associated with the menopause, start therapy with Vivelle-Dot 0.0375 mg/day applied to the skin twice weekly.

For the prevention of postmenopausal osteoporosis, start therapy with Vivelle-Dot 0.025 mg/day applied to the skin twice weekly.

The dosage may be adjusted as necessary.

Reproductive system-associated adverse events were encountered more frequently in the highest dose group (0.1 mg/day) than in other active treatment groups or in placebo-treated patients.

In women not currently taking oral estrogens or in women switching from another estradiol transdermal therapy, treatment with Vivelle-Dot may be initiated at once.

In women who are currently taking oral estrogens, treatment with Vivelle-Dot should be initiated 1 week after withdrawal of oral hormone therapy, or sooner if menopausal symptoms reappear in less than 1 week.

Therapeutic Regimen Vivelle-Dot may be given continuously in patients who do not have an intact uterus.

In those patients with an intact uterus, Vivelle-Dot may be given on a cyclic schedule (e.g., three weeks on drug followed by one week off drug).

DOSAGE AND ADMINISTRATION

The tablet dispenser has been designed to make oral contraceptive dosing as easy and as convenient as possible.

The tablets are arranged in four rows of seven tablets each, with the days of the week appearing on the tablet dispenser above the first row of tablets.

Note: Each tablet dispenser has been preprinted with the days of the week, starting with Sunday, to facilitate a Sunday-Start regimen.

Six different day label strips have been provided with the Detailed Patient & Brief Summary Patient Package Insert in order to accommodate a Day-1 Start regimen.

If the patient is using the Day-1 Start regimen, she should place the self-adhesive day label strip that corresponds to her starting day over the preprinted days.

Important: The patient should be instructed to use an additional method of protection until after the first week of administration in the initial cycle when utilizing the Sunday-Start regimen.

The possibility of ovulation and conception prior to initiation of use should be considered.

Dosage and Administration for 28-Day Dosage Regimen To achieve maximum contraceptive effectiveness, Tilia Fe should be taken exactly as directed and at intervals not exceeding 24 hours.

Tilia Fe provides a continuous administration regimen consisting of 21 active tablets of norethindrone acetate and ethinyl estradiol and 7 brown, non-hormone containing tablets of ferrous fumarate.

The ferrous fumarate tablets are present to facilitate ease of drug administration via a 28-day regimen and do not serve any therapeutic purpose.

There is no need for the patient to count days between cycles because there are no “off-tablet days.” A.

Sunday-Start Regimen: The patient begins taking the first white tablet from the top row of the dispenser (labeled Sunday) on the first Sunday after menstrual flow begins.

When menstrual flow begins on Sunday, the first white tablet is taken on the same day.

The patient takes one active tablet daily for 21 days.

The last active (green) tablet in the dispenser will be taken on a Saturday.

Upon completion of all 21 active tablets, and without interruption, the patient takes one brown tablet daily for 7 days.

Upon completion of this first course of tablets, the patient begins a second course of 28-day tablets, without interruption, the next day (Sunday), starting with the Sunday white tablet in the top row.

Adhering to this regimen of one active tablet daily for 21 days, followed without interruption by one brown tablet daily for 7 days, the patient will start all subsequent cycles on a Sunday.

B.

Day-1 Start Regimen: The first day of menstrual flow is Day 1.

The patient places the self-adhesive day label strip that corresponds to her starting day over the preprinted days on the tablet dispenser.

She starts taking one active tablet daily, beginning with the first white tablet in the top row.

After the last active, green tablet (at the end of the third row) has been taken, the patient will then take the brown tablets for a week (7 days).

For all subsequent cycles, the patient begins a new 28 tablet regimen on the eighth day after taking her last active tablet, again starting with the first tablet in the top row after placing the appropriate day label strip over the preprinted days on the tablet dispenser.

Following this regimen of 21 active tablets and 7 inactive, brown tablets, the patient will start all subsequent cycles on the same day of the week as the first course.

Tablets should be taken regularly at the same time each day and can be taken without regard to meals.

It should be stressed that efficacy of medication depends on strict adherence to the dosage schedule.

Special Notes on Administration Menstruation usually begins two or three days, but may begin as late as the fourth or fifth day, after the brown tablets have been started.

In any event, the next course of tablets should be started without interruption.

If spotting occurs while the patient is taking white tablets, continue medication without interruption.

If the patient forgets to take one or more active tablets, the following is suggested: One tablet is missed take tablet as soon as remembered take next tablet at the regular time Two consecutive tablets are missed (Week 1 or Week 2) take two tablets as soon as remembered take two tablets the next day use another birth control method for seven days following the missed tablets Two consecutive tablets are missed (Week 3) Sunday-Start Regimen: take one tablet daily until Sunday discard remaining tablets start new pack of tablets immediately (Sunday) use another birth control method for seven days following the missed tablets Day-1 Start Regimen: discard remaining tablets start new pack of tablets that same day use another birth control method for seven days following the missed tablets Three (or more) consecutive tablets are missed Sunday-Start Regimen: take one tablet daily until Sunday discard remaining tablets start new pack of tablets immediately (Sunday) use another birth control method for seven days following the missed tablets Day-1 Start Regimen: discard remaining tablets start new pack of tablets that same day use another birth control method for seven days following the missed tablets The possibility of ovulation occurring increases with each successive day that scheduled active tablets are missed.

While there is little likelihood of ovulation occurring if only one active tablet is missed, the possibility of spotting or bleeding is increased.

This is particularly likely to occur if two or more consecutive active tablets are missed.

If the patient forgets to take any of the seven brown tablets in week four, those brown tablets that were missed are discarded and one brown tablet is taken each day until the pack is empty.

A back-up birth control method is not required during this time.

A new pack of tablets should be started no later than the eighth day after the last active tablet was taken.

In the rare case of bleeding which resembles menstruation, the patient should be advised to discontinue medication and then begin taking tablets from a new tablet dispenser on the next Sunday or the first day (Day-1) depending on her regimen.

Persistent bleeding which is not controlled by this method indicates the need for re-examination of the patient, at which time nonfunctional causes should be considered.

Use of Oral Contraceptives in the Event of a Missed Menstrual Period If the patient has not adhered to the prescribed dosage regimen, the possibility of pregnancy should be considered after the first missed period and oral contraceptives should be withheld until pregnancy has been ruled out.

If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen.

After several months on treatment, bleeding may be reduced to a point of virtual absence.

This reduced flow may occur as a result of medication, in which event it is not indicative of pregnancy.

Acne The timing of initiation of dosing with Tilia Fe for acne should follow the guidelines for use of Tilia Fe as an oral contraceptive.

Consult the section for oral contraceptives.

DOSAGE AND ADMINISTRATION

Directions drink a full glass of water with each dose adults and children 12 years and over: take 4 to 8 tablets every 4 hours not to exceed 48 tablets in 24 hours unless directed by a doctor children under 12 years: consult a doctor

DOSAGE AND ADMINISTRATION

Directions Adults and children 12 years of age or older: Rub this soothing cream on the affected area not more that 3 to 4 times daily.

Children under the age of 12: Do not use, consult a doctor.