Arzerra

Unless your doctor tells you otherwise, continue your normal diet.

1. Arzerra

• Glaxo SmithKline Pharmaceuticals

• GlaxoSmithKline LLC

Before taking Arzerra, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to Arzerra or to any of its ingredients
• have or have had hepatitis B infection
• have chronic obstructive pulmonary disease (COPD)
• are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Dosage Forms & Strengths

injectable solution

• 100mg/5mL vial
• 1000mg/50mL vial

Chronic Lymphocytic Leukemia

Previously untreated

• In combination with chlorambucil for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate
• Cycle 1: 300 mg IV on Day 1 followed 1 week later by 1,000 mg on Day 8, THEN
• Subsequent 28-day cycles: 1,000 mg on Day 1 for a minimum of 3 cycles until best response or a maximum of 12 cycles

Relapsed CLL

• Indicated in combination with fludarabine and cyclophosphamide for relapsed CLL
• Dose 1: 300 mg IV, followed 1 week later by
• Dose 2: 1,000 mg IV, followed by
• Dose 3 and thereafter: 1,000 mg on Day 1 of subsequent 28-day cycles for maximum of 6 cycles

Extended treatment

• Indicated for extended treatment as a single agent in patients who are in complete or partial response after at least 2 lines of therapy for recurrent or progressive CLL
• Dose 1: 300 mg IV on Day 1, followed 1 week later by
• Dose 2: 1,000 mg 1 week on Day 8, followed 7 weeks later by
• Dose 3 and thereafter: 1,000 mg IV and then q8wk thereafter for up to a maximum of 2 yr

Refractory CLL

• Indicated for CLL refractory to fludarabine and alemtuzumab
• Dose 1: 300 mg IV, followed 1 week later by
• Doses 2-8: 2,000 mg IV qWeek for 7 doses, followed 4 weeks later by
• Doses 9-12: 2,000 mg IV q4Weeks for 4 doses
• Regimen totals 12 doses

Safety and efficacy not established

>10%

Neutropenia

Pneumonia

Pyrexia

Cough

Diarrhea

Anemia

Fatigue

Dyspnea

Rash

Nausea

Bronchitis

Upper respiratory tract infections

<10%

Infusion reaction/complication

Cytopenias

Infection (pneumonia, sepsis)

Progressive multifocal leukoencephalopathy

Hepatitis B reactivation

Intestinal obstruction

Ofatumumab is injected into a vein through an IV. A healthcare provider will give you this injection. The medicine must be given slowly through an IV infusion, and one dose can take up to several hours to complete.

Ofatumumab is usually given in a treatment cycle over several weeks, beginning with one infusion per week. Then you will receive your infusions less often, depending on the type of CLL for which you are being treated.

Your dosing schedule may change with further doses. Your doctor will determine how long to treat you with ofatumumab.

You will be given other IV or oral (by mouth) medications to prevent certain side effects of ofatumumab. You may need to start using these medications up to 2 hours before the start of your ofatumumab infusion.

You may also need to take antiviral medications if you are found to have any risk factors for hepatitis B. Follow your doctor's dosing instructions very carefully. Ofatumumab can cause hepatitis B to come back or get worse. You will need frequent blood tests to check your liver function.

Ofatumumab can have long lasting effects on your body. You may also need medical tests for a short time after you stop using this medication.

If you have hepatitis B you may develop liver symptoms after you stop taking this medication, even months after stopping. Your doctor may want to check your liver function for several months after you stop using ofatumumab.

Antineoplastic agent; a recombinant fully human anti-CD20 monoclonal antibody.1 3 5 6 8 9

Absorption

Onset

Median decrease in circulating CD19+ B-cells after doses 8 and 12 in the 12-dose regimen was 91 and 85%, respectively, in patients with fludarabine- and alemtuzumab-refractory B-CLL.1

Duration

Time required for lymphocytes, including CD19+ B-cells, to recover to normal levels following ofatumumab therapy not fully determined.1

Distribution

Extent

Crosses the placenta in monkeys.1 Not known whether ofatumumab is distributed into milk (see Lactation under Cautions).1

Elimination

Elimination Route

Eliminated through both an antigen CD20-independent route and a B-cell-mediated route.1

Half-life

Approximately 14 days (range: 2–61 days) as determined between fourth and twelfth doses in patients with refractory CLL.1

After sequential doses, clearance is decreased substantially because of B-cell depletion.1

Special Populations

Pharmacokinetics not substantially affected by age (over range of 21–86 years), baseline Clcr (over range of 33–287 mL/minute), sex, or body weight.1

Storage

Parenteral

2–8°C.1 Do not freeze.1 Protect vials from light.1

Following dilution, 2–8°C;1 discard after 24 hours.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

No incompatibilities observed with PVC or polyolefin bags and administration sets.1

Ofatumumab injection is used in combination with chlorambucil to treat a type of cancer of the white blood cells called chronic lymphocytic leukemia (CLL) in patients who have not received any treatments in the past. It is also used in combination with fludarabine and cyclophosphamide to treat patients with relapsed CLL. This medicine is also used in patients with CLL who have already been treated with other medicines (eg, alemtuzumab, fludarabine) that did not work well.

Ofatumumab interferes with the growth of cancer cells, which are eventually destroyed by the body. Since the growth of normal body cells may also be affected by ofatumumab, other unwanted effects will also occur. Some of these may be serious and must be reported to your doctor. Some unwanted effects, such as a skin rash, may not be serious but may cause concern. Some of the unwanted effects do not occur until months or years after the medicine is used.

Before you begin treatment with ofatumumab, you and your doctor should talk about the benefits this medicine will do as well as the risks of using it.

This medicine is to be given only by or under the direct supervision of your doctor.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of ofatumumab injection in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of ofatumumab injection in the elderly. However, elderly patients are more likely to have unwanted side effects (eg, neutropenia, pneumonia) which may require caution.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Measles Virus Vaccine, Live
• Mumps Virus Vaccine, Live
• Rotavirus Vaccine, Live
• Rubella Virus Vaccine, Live
• Varicella Virus Vaccine

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Adenovirus Vaccine
• Bacillus of Calmette and Guerin Vaccine, Live
• Cholera Vaccine, Live
• Influenza Virus Vaccine, Live
• Poliovirus Vaccine, Live
• Smallpox Vaccine
• Typhoid Vaccine
• Yellow Fever Vaccine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Hepatitis B, or history of—Use with caution. May make this condition worse.

• Infection—May decrease your body's ability to fight infection.

• If you have an allergy to ofatumumab or any other part of Arzerra.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Tell all of your health care providers that you take Arzerra. This includes your doctors, nurses, pharmacists, and dentists.
• You may have more of a chance of getting an infection. Wash hands often. Stay away from people with infections, colds, or flu. Some infections have been very bad and even deadly.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Talk with your doctor before getting any vaccines. Use with this medicine may either raise the chance of an infection or make the vaccine not work as well.
• If you are 65 or older, use Arzerra with care. You could have more side effects.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
• If you used Arzerra when you were pregnant, tell your baby's doctor.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

     Pregnancy

Risk Summary

Arzerra may cause fetal B-cell depletion based on findings from animal studies and the drug’s mechanism of action [see Clinical Pharmacology (12.1)]. There are no data on Arzerra use in pregnant women to inform a drug-associated risk. However, there are clinical considerations [see Clinical Considerations]. No teratogenicity was observed in animal reproduction studies with administration of Arzerra to pregnant monkeys during organogenesis at doses 0.3 and 2.4 times the maximum recommended human dose (MRHD) of 2000 mg based on monkey geometric mean AUCinf of 213 mg.h/mL and 1646 mg.h/mL, respectively. However, ofatumumab caused depletion of maternal circulating B-cells, depletion of peripheral and splenic fetal B-cells, and decreased fetal spleen weights [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies, respectively.

Clinical Considerations

Fetal/neonatal adverse reactions

Arzerra may cause fetal B-cell depletion [see Data]. Avoid administering live vaccines to neonates and infants exposed to Arzerra in utero until B-cell recovery occurs [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.2)].

Data

Animal Data

In an embryo-fetal development study, pregnant cynomolgus monkeys received 20 or 100 mg/kg/day of ofatumumab intravenously (30 minute infusion) once weekly during the period of organogenesis [Gestation Days (GD) 20 to 50] with systemic exposure throughout pregnancy due to the long half-life as drug was detected in maternal serum on GD 100 (early fetal period of development). At the end of organogenesis on GD 48, the exposure in pregnant monkeys receiving ofatumumab 20 and 100 mg/kg/day was approximately 0.3 and 2.4 times the human exposure after the 8th infusion of the MRHD of 2,000 mg based on monkey geometric mean AUCinf of 213 mg.h/mL and 1,646 mg.h/mL, respectively. Ofatumumab crossed the placenta, as it was detected in fetal cord blood on GD 100 in both dose groups. There was no maternal toxicity and no effect on pregnancy success. As expected, both dose levels of ofatumumab depleted circulating B cells in the mothers; recovery of B lymphocytes in dosed animals was not observed during the dosing-free period. Following Caesarean section at GD 100, fetuses from treated mothers exhibited decreases in mean peripheral and splenic B-cell counts (decreased to approximately 12% and 15% of control values at both dose levels, respectively and spleen weights (decreased by approximately 15% in low-dose group and by approximately 30% in high-dose group, compared with control values). There was no effect on prenatal survival and no evidence of teratogenicity in this monkey study.

The kinetics of B-lymphocyte recovery and the potential long-term effects of perinatal B-cell depletion in offspring from ofatumumab-treated maternal monkeys have not been studied.

     Lactation

Risk Summary

There is no information regarding the presence of Arzerra in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG is known to be present in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Arzerra and any potential adverse effects on the breastfed infant from Arzerra or from the underlying maternal condition.

     Pediatric Use

Safety and effectiveness of Arzerra have not been established in children.

     Geriatric Use

In patients with previously untreated CLL (Study 1), 68% (148/217) receiving Arzerra plus chlorambucil were 65 years and older. Patients age 65 years and older experienced a higher incidence of the following Grade 3 or greater adverse reactions compared with patients younger than 65 years of age: neutropenia (30% versus 17%) and pneumonia (5% versus 1%) [see Adverse Reactions (6.1)]. In patients 65 years and older, 29% experienced serious adverse events compared with 13% of patients younger than 65 years. No clinically meaningful differences in the effectiveness of Arzerra plus chlorambucil were observed between older and younger patients [see Clinical Studies (14.1)].

In patients with relapsed CLL (Study 2), 33% (60/181) of patients receiving Arzerra plus fludarabine and cyclophosphamide were 65 years and older. No clinically meaningful differences in the safety or effectiveness of Arzerra were observed between patients age 65 years and older, and those younger than 65 years [see Adverse Reactions (6.1), Clinical Studies (14.2)].

With extended treatment in patients with CLL (Study 3), 49% (117/237) receiving Arzerra were 65 years and older. No clinically meaningful differences in the safety or effectiveness of Arzerra were observed between patients age 65 years and older and those younger than 65 years of age [see Adverse Reactions (6.1), Clinical Studies (14.3)].

In refractory CLL clinical studies there were insufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients [see Clinical Pharmacology (12.3)].