DRUG INTERACTIONS-

 No drug-drug interaction studies have been conducted with dinutuximab.

BRIEF SUMMARY

DINUTUXIMAB-(Mar 2015)

Indn-      to treat pediatric patients with high risk neuroblastoma

Comp-      • Injection: 17.5 mg/5 mL (3.5 mg/mL) in a single-use vial. • 17.5 mg/m2/day as a diluted intravenous infusion over 10 to 20 hours for 4 consecutive days for up to 5 cycles.

ADR-      The most common adverse drug reactions (= 25%) are pain, pyrexia, thrombocytopenia, lymphopenia, infusion reactions, hypotension, hyponatremia, increased alanine aminotransferase, anemia, vomiting, diarrhea, hypokalemia, capillary leak syndrome, neutropenia, urticaria, hypoalbuminemia, increased aspartate aminotransferase, and hypocalcemia.

CI-   • History of anaphylaxis to dinutuximab.

WARNINGS-

 • Capillary leak syndrome and hypotension: Administer required prehydration and monitor patients closely during treatment. Depending upon severity, manage by interruption, infusion rate reduction, or permanent discontinuation

Pat Infrm-

• Serious Infusion Reactions-                                                                                   Inform patients and caregivers of the risk of serious infusion reactions and anaphylaxis and to immediately report any signs or symptoms, such as facial or lip swelling, urticaria, difficulty breathing, lightheadedness or dizziness that occur during or within 24 hours following the infusion 

• Pain and Peripheral Neuropathy -                                                                                      Inform patients and caregivers of the risk of severe pain and peripheral sensory and motor neuropathy and to promptly report severe or worsening pain and signs and symptoms of neuropathy such as numbness, tingling, burning, or weakness

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Novel Drug Approvals for 2015

1.Name                        UNTUXIM

2.Active ingredient-    Dinutuximab

3. Indication-            to treat pediatric patients with high risk neuroblastoma

Date of Approval       3/10/2015

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use UNITUXIN safely and effectively.

See Full Prescribing Information for UNITUXIN. UNITUXIN™ (dinutuximab) injection, for intravenous use

Initial U.S. Approval: 2015

WARNING:

SERIOUS INFUSION REACTIONS AND NEUROPATHY See full prescribing information for complete boxed warning.

• Infusion Reactions: Life-threatening infusion adverse reactions occur with Unituxin. Administer required prehydration and premedication. Immediately interrupt for severe infusion reactions and permanently discontinue for anaphylaxis

 • Neuropathy: Unituxin causes severe neuropathic pain. Administer intravenous opioid prior to, during, and for 2 hours following completion of the Unituxin infusion.

INDICATIONS AND USAGE -

 Unituxin is a GD2-binding monoclonal antibody indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy. 

ADVERSE REACTIONS -

 The most common adverse drug reactions (= 25%) are pain, pyrexia, thrombocytopenia, lymphopenia, infusion reactions, hypotension, hyponatremia, increased alanine aminotransferase, anemia, vomiting, diarrhea, hypokalemia, capillary leak syndrome, neutropenia, urticaria, hypoalbuminemia, increased aspartate aminotransferase, and hypocalcemia.

CONTRAINDICATIONS-

• History of anaphylaxis to dinutuximab.

WARNINGS AND PRECAUTIONS-

 • Capillary leak syndrome and hypotension: Administer required prehydration and monitor patients closely during treatment. Depending upon severity, manage by interruption, infusion rate reduction, or permanent discontinuation

 • Infection: Interrupt until resolution of systemic infection.

 • Neurological Disorders of the Eye: Interrupt for dilated pupil with sluggish light reflex or other visual disturbances and permanently discontinue for recurrent eye disorders or loss of vision.

 • Bone marrow suppression: Monitor peripheral blood counts during Unituxin therapy.

 • Electrolyte abnormalities: Monitor serum electrolytes closely.

 • Atypical hemolytic uremic syndrome: Permanently discontinue Unituxin and institute supportive management.

 • Embryo-Fetal toxicity:                                                                                                May cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception.

DOSAGE AND ADMINISTRATION -

 • 17.5 mg/m2/day as a diluted intravenous infusion over 10 to 20 hours for 4 consecutive days for up to 5 cycles. 

DOSAGE FORMS AND STRENGTHS -

 • Injection: 17.5 mg/5 mL (3.5 mg/mL) in a single-use vial.

 PATIENT COUNSELING INFORMATION

• Serious Infusion Reactions-                                                                                   Inform patients and caregivers of the risk of serious infusion reactions and anaphylaxis and to immediately report any signs or symptoms, such as facial or lip swelling, urticaria, difficulty breathing, lightheadedness or dizziness that occur during or within 24 hours following the infusion 

• Pain and Peripheral Neuropathy -                                                                                      Inform patients and caregivers of the risk of severe pain and peripheral sensory and motor neuropathy and to promptly report severe or worsening pain and signs and symptoms of neuropathy such as numbness, tingling, burning, or weakness

• Capillary Leak Syndrome -                                                                                        Inform patients and caregivers of the risk of capillary leak syndrome and to immediately report any signs or symptoms 

. • Hypotension-                                                                                                           Inform patients and caregivers of the risk of hypotension during the infusion and to immediately report any signs or symptoms 

• Infection-                                                                                                                  Inform patients and caregivers of the risk of infection following treatment and to immediately report any signs or symptoms 

• Neurological Disorders of the Eye-                                                                                Inform patients and caregivers of the risk of neurological disorders of the eye and to promptly report signs or symptoms such as blurred vision, photophobia, ptosis, diplopia, or unequal pupil size 

• Bone Marrow Suppression-                                                                                            Inform patients and caregivers of the risk of bone marrow suppression, and to promptly report signs or symptoms of anemia, thrombocytopenia, or infection

• Electrolyte Abnormalities-                                                                                         Inform patients and caregivers of the risk of electrolyte abnormalities including hypokalemia, hyponatremia, and hypocalcemia, and to report any signs or symptoms such as seizures, heart palpitations, and muscle cramping

• Atypical Hemolytic Uremic Syndrome-                                                                          Inform patients and caregivers of the risk of hemolytic uremic syndrome and to report any signs or symptoms such as fatigue, dizziness, fainting, pallor, edema, decreased urine output, or hematuria 

• Embryo-Fetal Toxicity-                                                                                                    Advise women of reproductive potential of the potential risk to the fetus if administered during pregnancy and the need for use of effective contraception during and for at least two months after completing therapy

United Therapeutics Corp. All rights reserved. Unituxin manufactured by: United Therapeutics Corp. Silver Spring, MD 20910 US License

CLINICAL PHARMACOLOGY

1. Mechanism of Action-

Dinutuximab binds to the glycolipid GD2. This glycolipid is expressed on neuroblastoma cells and on normal cells of neuroectodermal origin, including the central nervous system and peripheral nerves.

Dinutuximab binds to cell surface GD2 and induces cell lysis of GD2 expressing cells through antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

3. Pharmacokinetics-

The pharmacokinetics of dinutuximab was evaluated by a population pharmacokinetic analysis in a clinical study of Unituxin in combination with GM-CSF, IL-2, and RA.

The mean volume of distribution at steady state (Vd ss) was 5.4 L (28%).

The clearance was 0.21 L/day (62%) and increased with body size.

The terminal half-life was 10 days (56%). No formal pharmacokinetic studies were conducted in patients with renal or hepatic impairment.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-

Based on its mechanism of action, Unituxin may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)].

There are no studies in pregnant women and no reproductive studies in animals to inform the drug-associated risk. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester

. Advise pregnant women of the potential risk to a fetus.

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

2. Lactation Risk Summary-                                                                                          There is no information available on the presence of dinutuximab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. However, human IgG is present in human milk

 Because of the potential for serious adverse reactions in a breastfed infant, advise a nursing woman to discontinue breastfeeding during treatment with Unituxin.

3. Females and Males of Reproductive Potential-

Contraception Females- Unituxin may cause fetal harm 

Advise females of reproductive potential to use effective contraception during treatment and for two months after the last dose of Unituxin.

4. Pediatric Use-                                                                                                              The safety and effectiveness of Unituxin as part of multi-agent, multimodality therapy have been established in pediatric patients with high-risk neuroblastoma based on results of an open-label, randomized (1:1) trial conducted in 226 patients aged 11 months to 15 years (median age 3.8 years.

5. Geriatric Use-                                                                                                               The safety and effectiveness of Unituxin in geriatric patients have not been established.

6 Renal Impairment -                                                                                                  Unituxin has not been studied in patients with renal impairment.

7. Hepatic Impairment -                                                                                          Unituxin has not been studied in patients with hepatic impairment.