Marqibo

Generic Name: vincristine sulfate liposome injection
Date of Approval: August 9, 2012
Company: Talon Therapeutics, Inc.
Treatment for: Philadelphia Chromosome-Negative (Ph-) Acute Lymphoblastic Leukemia

FDA Approves Marqibo

The U.S. Food and Drug Administration (FDA) has approved Marqibo (vincristine sulfate liposome injection) for the treatment of adult patients with Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following two or more anti-leukemia therapies.

Marqibo is a novel, sphingomyelin/cholesterol liposome-encapsulated, formulation of vincristine sulfate. Vincristine, a microtubule inhibitor, is FDA-approved for ALL and Non-Hodgkin's Lymphoma (NHL) and is widely used in combination regimens for treatment for a variety of adult and pediatric hematologic and solid tumor malignancies. The Optisome™ nanoparticle encapsulation technology, utilized by the manufacturer Talon Therapeutics, Inc., has been shown to provide prolonged circulation of vincristine in the blood.

Marqibo has received orphan drug designation for the treatment of ALL from the FDA.

Important Safety Information for Marqibo

Contraindications

Marqibo is contraindicated:

• in patients with demyelinating conditions including Charcot-Marie-Tooth syndrome
• in patients with hypersensitivity to vincristine sulfate or any of the other components of Marqibo
• for intrathecal administration

Warnings and Precautions

• For Intravenous use only. Fatal if given by other routes. Death has occurred with intrathecal use
• Marqibo (vincristine sulfate liposome injection) has different dosage recommendations than vincristine sulfate injection. Verify drug name and dose prior to preparation and administration to avoid overdosage.

Extravasation Tissue Injury

Only administer through a secure and free‑flowing venous access line. If extravasation is suspected, discontinue infusion immediately and consider local treatment measures.

Neurologic Toxicity

Sensory and motor neuropathies are common and are cumulative. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, hyporeflexia, areflexia, neuralgia, jaw pain, decreased vibratory sense, cranial neuropathy, ileus, burning sensation, arthralgia, myalgia, muscle spasm, or weakness, both before and during treatment. Orthostatic hypotension may occur. The risk of neurologic toxicity is greater if Marqibo is administered to patients with preexisting neuromuscular disorders or when other drugs with risk of neurologic toxicity are being given. In the studies of relapsed and/or refractory adult ALL patients, Grade ≥ 3 neuropathy events occurred in 32.5% of patients. Worsening neuropathy requires dose delay, reduction, or discontinuation of Marqibo.

MyelosuppressionMonitor complete blood counts prior to each dose of Marqibo. If Grade 3 or 4 neutropenia, thrombocytopenia, or anemia develops, consider Marqibo dose modification or reduction as well as supportive care measures.

Tumor Lysis Syndrome

Tumor lysis syndrome (TLS) may occur in patients with ALL receiving Marqibo. Anticipate, monitor for, and manage.

Constipation and Bowel Obstruction

Ileus, bowel obstruction, and colonic pseudo‑obstruction have occurred. Marqibo can cause constipation. Institute a prophylactic bowel regimen to mitigate potential constipation, bowel obstruction, and/or paralytic ileus, considering adequate dietary fiber intake, hydration, and routine use of stool softeners, such as docusate. Additional treatments, such as senna, bisacodyl, milk of magnesia, magnesium citrate, and lactulose may be considered.

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Fatigue

Marqibo can cause severe fatigue. Marqibo dose delay, reduction, or discontinuation may be necessary.

Hepatic Toxicity

Fatal liver toxicity and elevated levels of aspartate aminotransferase have occurred. Elevated levels of aspartate aminotransferase of Grade ≥3 occurred in 6‑11% of patients in clinical trials. Monitor hepatic function tests. Reduce or interrupt Marqibo for hepatic toxicity.

Embryofetal Toxicity

Marqibo can cause fetal harm when administered to a pregnant woman. Vincristine sulfate liposome injection was teratogenic or caused embryo‑fetal death in animals. Women of childbearing potential should avoid becoming pregnant while being treated with Marqibo. There are no adequate and well‑controlled studies of Marqibo in pregnant women and there were no reports of pregnancy in any of the clinical studies in the Marqibo clinical development program. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Adverse Reactions

The most common adverse reactions ( > 30%) were constipation (57%), nausea (52%), pyrexia (43%), fatigue (41%), peripheral neuropathy (39%), febrile neutropenia (38%), diarrhea (37%), anemia (34%), decreased appetite (33%), and insomnia (32%).

The most commonly reported SAEs included febrile neutropenia (20.5%), pyrexia (13.3%), hypotension (7.2%), respiratory distress (6.0%), and cardiac arrest (6.0%).

Twenty-eight percent of patients experienced adverse reactions leading to treatment discontinuation. The most common adverse reactions that caused treatment discontinuation were peripheral neuropathy (10%), leukemia‑related (7%), and tumor lysis syndrome (2%).

Deaths occurred in 23% of patients in study 1. The non-leukemia related causes of deaths were brain infarct (1), intracerebral hemorrhage (2), liver failure (1), multi-system organ failure (2), pneumonia and septic shock (3), respiratory failure (4), pulmonary hemorrhage (1), and sudden cardiac death (1).

Drug Interactions

No formal drug interaction studies have been conducted with Marqibo. Marqibo is expected to interact with drugs known to interact with non‑liposomal vincristine sulfate.

Simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included non‑liposomal vincristine sulfate has been reported to reduce blood levels of phenytoin and to increase seizure activity.

CYP3A Interactions

Vincristine sulfate, the active agent in Marqibo, is a substrate for cytochrome P450 3A isozymes (CYP3A); therefore, the concomitant use of strong CYP3A inhibitors should be avoided (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin). Similarly, the concomitant use of strong CYP3A inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John's Wort).

P‑glycoprotein Interactions

Vincristine sulfate, the active agent in Marqibo, is also a substrate for P‑glycoprotein (P‑gp). The effect of concomitant use of potent P‑gp inhibitors or inducers has not been investigated; it is likely that these agents will alter the pharmacokinetics or pharmacodynamics of Marqibo. Therefore the concomitant use of potent P‑gp inhibitors or inducers should be avoided.

Use in Specific Populations

Pregnancy

Pregnancy Category D

Based on its mechanism of action and findings from animal studies, Marqibo can cause fetal harm when administered to pregnant women.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. In an embryofetal developmental study, pregnant rats were administered vincristine sulfate liposome injection intravenously during the period of organogenesis at vincristine sulfate doses of 0.022 to 0.09 mg/kg/day. Drug‑related adverse effects included fetal malformations (skeletal and visceral), decreases in fetal weights, increased numbers of early resorptions and post‑implantation losses, and decreased maternal body weights Malformations were observed at doses ≥ 0.044 mg/kg/day in animals at systemic exposures approximately 20‑40% of those reported in patients at the recommended dose.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of Marqibo in pediatric patients have not been established.

Geriatric Use

Safety and effectiveness in elderly individuals have not been established. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal Impairment

The influence of renal impairment on the safety, efficacy, and pharmacokinetics of Marqibo has not been evaluated.

Hepatic Impairment

Non‑liposomal vincristine sulfate is excreted primarily by the liver. The influence of severe hepatic impairment on the safety and efficacy of Marqibo has not been evaluated. The pharmacokinetics of Marqibo was evaluated in patients with moderate hepatic dysfunction (Child‑Pugh B) secondary to melanoma liver metastases. The dose‑adjusted maximum plasma concentration (Cmax) and area under the concentration‑time curve (AUC) of Marqibo in patients with moderate hepatic impairment was comparable to the Cmax and AUC of patients with ALL who had otherwise normal hepatic function.

Marqibo Patient Information

Read this Patient Information before you begin receiving Marqibo and before each Marqibo infusion. There may be new information. This information does not take the place of you talking with your doctor about your medical condition or treatment.

What is Marqibo?

Marqibo is a prescription medicine used to treat adults with Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) when:

• their leukemia has come back (relapsed) after 2 or more anti-leukemia therapies, or
• their leukemia became worse (progressed) after two or more anti- leukemia therapies.

It is not known if Marqibo is safe and effective in children or in elderly adults.

Do not receive Marqibo:

• if you have certain conditions of the brain or spinal cord, including Charcot- Marie-Tooth syndrome. Talk to your doctor before receiving Marqibo if you have a condition that affects your brain or spinal cord.
• if you are allergic to vincristine sulfate or any of the ingredients in Marqibo. See end of this page for a list of the ingredients in Marqibo.
• as an injection into your spine (intrathecal). Marqibo causes death if given by any route other than by intravenous (IV) infusion.

Before receiving Marqibo

Before receiving Marqibo, tell your doctor if you:

• have had treatment containing vincristine sulfate in the past
• currently have numbness or tingling in your feet or hands or decreased sensitivity to heat, cold, or pain
• have difficulty walking or picking up and holding items with your hands
• have a change in bowel regularity or constipation, and difficulty passing urine
• have head or jaw pain
• have liver problems
• are pregnant or plan to become pregnant. Marqibo can harm your unborn baby. You should not become pregnant while taking Marqibo. Use an effective method of birth control during treatment with Marqibo. Tell your doctor right away if you become pregnant while taking Marqibo.
• are breastfeeding or plan to breastfeed. It is not known if Marqibo passes into your milk. You and your doctor should decide whether you will take Marqibo or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Marqibo may affect the way other medicines work, and other medicines may affect how Marqibo works.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How will I receive Marqibo?

• You will receive Marqibo as an intravenous (IV) infusion in your vein over 1 hour. Marqibo is usually given every 7 days.,/li>
• Your doctor may change your dose, give you Marqibo less often, or stop your treatment with Marqibo if you have certain side effects.
• Your doctor should do blood tests regularly to check for side effects of Marqibo.

What should I avoid while receiving Marqibo?

• Marqibo can cause tiredness (fatigue) and nerve problems (neuropathy). You should not drive or operate machinery if you develop any of these symptoms. See Marqibo side effects.

Marqibo side effects

Marqibo can cause serious side effects, including:

• Tissue injury. If Marqibo leaks from your vein into the tissues around your intravenous (IV) line, it can cause damage to those tissues. Tell your doctor or nurse right away if you develop burning, redness or swelling at your IV site during or after your infusion.
• Nerve problems (neuropathy). Nerve problems are common with Marqibo and may get worse over time. Your doctor may need to change your dose, or delay or stop your treatment with Marqibo if you develop nerve problems. Symptoms may include:
  • numbness and tingling, or burning in your feet or hands
  • increased or decreased feeling of sensation to pain, touch, heat, or cold in your feet or hands
  • joint and muscle pain
  • pain in your jaw or head
  • muscle spasms
  • weakness in the hands or feet
  • dizziness or feel faint when you go from lying down to sitting, or from sitting to standing.
  • trouble picking up or holding items with your hands
  • slapping or dropping of the front part of your foot when walking forward (footdrop)
  • unsteadiness when standing or walking
  • difficulty speaking
  • constipation or a change from the normal regularity of your bowel movements
  • difficulty passing urine
  • difficulty with erection or ejaculation in men
• Low blood cell counts. Marqibo may cause you to have low red blood cells (anemia), low white blood cells (neutropenia), and low platelets (thrombocytopenia). Your doctor should do blood tests to check your blood cell counts before each dose of Marqibo. Your doctor may need to change your dose of Marqibo and treat your low blood cell counts if needed. Tell your doctor if you develop fever or cough up phlegm (productive cough).
• Tumor lysis syndrome (TLS). TLS is caused by a fast breakdown of cancer cells. TLS can cause you to have:
  • kidney failure and the need for dialysis treatment
  • an abnormal heart beat
  Your doctor will check you for TLS during treatment with Marqibo, and treat you for this problem if it happens.
• Constipation and intestinal (bowel) blockage. Your doctor will prescribe a bowel regimen for you to help prevent constipation or intestinal blockage. Symptoms may include:
  • stomach area (abdomen) pain, bloating or diarrhea
  • nausea or vomiting
• Tiredness (fatigue). Marqibo can cause severe tiredness or weariness. Your doctor may need to change your dose, or delay or stop you treatment if this happens.
• Liver problems that can cause death. Marqibo can cause changes in liver function tests or more serious liver problems that can cause death. Your doctor:
  • will monitor your liver function test during treatment with Marqibo.
  • may change your dose or stop your treatment with Marqibo if you develop liver problems.

Common side effects of Marqibo include:

• nausea
• fever
• diarrhea
• decreased appetite
• sleep problems

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effect of Marqibo. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

See also: Marqibo side effects (in more detail)

General information about Marqibo

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. This leaflet summarizes the most important information you need to know about Marqibo.

If you would like more information about Marqibo, talk with your doctor. You can ask your pharmacist or doctor for information about Marqibo that is written for health professionals. For more information, go to www.MarqiboRX.com or call 1-888-292-9617.

What are the ingredients in Marqibo?

Active ingredient: vincristine sulfate

Inactive ingredients: mannitol, sphingomyelin, cholesterol, sodium citrate, citric acid, sodium phosphate and sodium chloride.