Ladakamycin

Myelodysplastic Syndromes (MDS)

Ladakamycin for Injection is indicated for treatment of patients with the following French-American-British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).

Ladakamycin belongs to the group of medicines known as antimetabolites. It is used to treat some kinds of cancer.

Ladakamycin interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by Ladakamycin, other effects will also occur. Some of these may be serious and must be reported to your doctor. Some effects may not occur for months or years after the medicine is used.

Ladakamycin is available only with your doctor's prescription.

First Treatment Cycle

The recommended starting dose for the first treatment cycle, for all patients regardless of baseline hematology laboratory values, is 75 mg/m² subcutaneously or intravenously, daily for 7 days. Patients should be premedicated for nausea and vomiting.

Complete blood counts, liver chemistries and serum creatinine should be obtained prior to first dose.

Subsequent Treatment Cycles

Cycles should be repeated every 4 weeks. The dose may be increased to 100 mg/m² if no beneficial effect is seen after 2 treatment cycles and if no toxicity other than nausea and vomiting has occurred. It is recommended that patients be treated for a minimum of 4 to 6 cycles. However, complete or partial response may require additional treatment cycles. Treatment may be continued as long as the patient continues to benefit.

Patients should be monitored for hematologic response and renal toxicities, and dosage delay or reduction as described below may be necessary.

Dosage Adjustment Based On Hematology Laboratory Values

• For patients with baseline (start of treatment) WBC ≥ 3.0 x10/L, dose adjustments should be based on nadir counts and bone marrow biopsy cellularity at the time of the nadir as noted below, unless there is clear improvement in differentiation (percentage of mature granulocytes is higher and ANC is higher than at onset of that course) at the time of the next cycle, in which case the dose of the current treatment should be continued.

If a nadir as defined in the table above has occurred, the next course of treatment should be given 28 days after the start of the preceding course, provided that both the WBC and the platelet counts are > 25% above the nadir and rising. If a > 25% increase above the nadir is not seen by day 28, counts should be reassessed every 7 days. If a 25% increase is not seen by day 42, then the patient should be treated with 50% of the scheduled dose.

Dosage Adjustment Based On Serum Electrolytes And Renal Toxicity

If unexplained reductions in serum bicarbonate levels to < 20 mEq/L occur, the dosage should be reduced by 50% on the next course. Similarly, if unexplained elevations of BUN or serum creatinine occur, the next cycle should be delayed until values return to normal or baseline and the dose should be reduced by 50% on the next treatment course.

Use In Geriatric Patients

Ladakamycin and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Preparation Of Ladakamycin

Ladakamycin is a cytotoxic drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing Ladakamycin suspensions.

If reconstituted Ladakamycin comes into contact with the skin, immediately and thoroughly wash with soap and water. If it comes into contact with mucous membranes, flush thoroughly with water.

The Ladakamycin vial is single-use and does not contain any preservatives. Unused portions of each vial should be discarded properly. Do not save any unused portions for later administration.

Instructions For Subcutaneous Administration

Ladakamycin should be reconstituted aseptically with 4 mL sterile water for injection. The diluents should be injected slowly into the vial. Vigorously shake or roll the vial until a uniform suspension is achieved. The suspension will be cloudy. The resulting suspension will contain Ladakamycin 25 mg/mL. Do not filter the suspension after reconstitution. Doing so could remove the active substance.

Preparation For Immediate Subcutaneous Administration

Doses greater than 4 mL should be divided equally into 2 syringes. The product may be held at room temperature for up to 1 hour, but must be administered within 1 hour after reconstitution.

Preparation For Delayed Subcutaneous Administration

The reconstituted product may be kept in the vial or drawn into a syringe. Doses greater than 4 mL should be divided equally into 2 syringes. The product must be refrigerated immediately. When Ladakamycin is reconstituted using water for injection that has not been refrigerated, the reconstituted product may be held under refrigerated conditions (2°C - 8°C, 36°F - 46°F) for up to 8 hours. When Ladakamycin is reconstituted using refrigerated (2°C - 8°C, 36°F - 46°F) water for injection, the reconstituted product may be stored under refrigerated conditions (2°C - 8°C, 36°F - 46°F) for up to 22 hours. After removal from refrigerated conditions, the suspension may be allowed to equilibrate to room temperature for up to 30 minutes prior to administration.

Subcutaneous Administration

To provide a homogeneous suspension, the contents of the dosing syringe must be re-suspended immediately prior to administration. To re-suspend, vigorously roll the syringe between the palms until a uniform, cloudy suspension is achieved.

Ladakamycin suspension is administered subcutaneously. Doses greater than 4 mL should be divided equally into 2 syringes and injected into 2 separate sites. Rotate sites for each injection (thigh, abdomen, or upper arm). New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, red, or hard.

Suspension Stability

Ladakamycin reconstituted with non-refrigerated water for injection for subcutaneous administration may be stored for up to 1 hour at 25°C (77°F) or for up to 8 hours between 2°C and 8°C (36°F and 46°F); when reconstituted with refrigerated (2°C - 8°C, 36°F - 46°F) water for injection, it may be stored for 22 hours between 2°C and 8°C (36°F and 46°F).

Instructions For

Intravenous Administration

Reconstitute the appropriate number of Ladakamycin vials to achieve the desired dose. Reconstitute each vial with 10 mL sterile water for injection. Vigorously shake or roll the vial until all solids are dissolved. The resulting solution will contain Ladakamycin 10 mg/mL. The solution should be clear.

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

Withdraw the required amount of Ladakamycin solution to deliver the desired dose and inject into a 50 -100 mL infusion bag of either 0.9% Sodium Chloride Injection or Lactated Ringer's Injection.

Intravenous Solution Incompatibility

Ladakamycin is incompatible with 5% Dextrose solutions, Hespan, or solutions that contain bicarbonate. These solutions have the potential to increase the rate of degradation of Ladakamycin and should therefore be avoided.

Intravenous Administration

Ladakamycin solution is administered intravenously. Administer the total dose over a period of 10 - 40 minutes. The administration must be completed within 1 hour of reconstitution of the Ladakamycin vial.

Solution Stability: Ladakamycin reconstituted for intravenous administration may be stored at 25°C (77°F), but administration must be completed within 1 hour of reconstitution.

How supplied

Dosage Forms And Strengths

Ladakamycin (Ladakamycin for injection) is supplied as lyophilized powder in 100 mg single-use vials.

Storage And Handling

Ladakamycin (Ladakamycin for injection) is supplied as a lyophilized powder in 100 mg single-use vials packaged in cartons of 1 vial (NDC 59572-102-01).

Storage

Store unreconstituted vials at 25° C (77° F); excursions permitted to 15°-30° C (59°-86° F).

Handling And Disposal

Procedures for proper handling and disposal of anticancer drugs should be applied. Several guidelines on this subject have been published.1 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Manufactured for: Celgene Corporation, Summit, NJ 07901. Manufactured by: Baxter Oncology GmbH, 33790 Halle/Westfalen Germany Or BSP Pharmaceuticals S.r.l., 04013 Latina Scalo (Lt)

See also:
What is the most important information I should know about Ladakamycin?

Do not use Ladakamycin if you are pregnant. It could harm the unborn baby.

You should not receive this medication if you are allergic to Ladakamycin or mannitol, or if you have liver cancer.

Before receiving Ladakamycin, tell your doctor if you have kidney disease, liver disease, or a history of liver cancer.

If a man fathers a baby while using Ladakamycin, the baby may have birth defects. Use a condom to prevent pregnancy during your treatment. Continue using condoms for at least 4 weeks after you stop using Ladakamycin.

Tell your caregiver right away if this medication accidentally gets on your skin. Wash the area thoroughly with soap and warm water.

Ladakamycin can lower blood cells that help your body fight infections and help your blood to clot. Your blood may need to be tested often. Avoid being near people who are sick or have infections. Avoid activities that may increase your risk of bleeding injury. Tell your doctor at once if you develop signs of infection.

Do not receive a "live" vaccine while you are being treated with Ladakamycin, and avoid coming into contact with anyone who has recently received a live vaccine. There is a chance that the virus could be passed on to you.

Use Ladakamycin as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Ladakamycin is usually given as an injection at your doctor's office, hospital, or clinic. If you will be using Ladakamycin at home, a health care provider will teach you how to use it. Be sure you understand how to use Ladakamycin. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.
• Do not use Ladakamycin if it contains particles, is discolored, or if the vial is cracked or damaged.
• You may receive certain other medicines before Ladakamycin to help decrease the risk of nausea and vomiting. Discuss any questions with your doctor.
• If Ladakamycin comes into contact with the skin, immediately and thoroughly wash it off with soap and water. If it comes into contact with mucous membranes (eg, eyes, nose, mouth, vagina), flush thoroughly with water.
• Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.
• If you miss a dose of Ladakamycin, contact your doctor right away.

Ask your health care provider any questions you may have about how to use Ladakamycin.

Use: Labeled Indications

Myelodysplastic syndromes: Treatment of myelodysplastic syndromes (MDS) in patients with the following French-American-British (FAB) classification subtypes: Refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia.

Off Label Uses

Acute myeloid leukemia (AML) in patients requiring low-intensity therapy

Data from a phase III randomized trial supports the use of Ladakamycin in the management of patients requiring low-intensity therapy for AML.

See also:
What other drugs will affect Ladakamycin?

No formal clinical assessments of drug-drug interactions between Ladakamycin and other agents have been conducted.

See also:
What are the possible side effects of Ladakamycin?

The following adverse reactions are described in other labeling sections:

• Anemia, neutropenia and thrombocytopenia
• Hepatic coma
• Elevated serum creatinine, renal failure, and renal tubular acidosis

Most Commonly Occurring Adverse Reactions (SC or IV Route): nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by IV route also included petechiae, rigors, weakness and hypokalemia.

Adverse Reactions Most Frequently ( > 2%) Resulting in Clinical Intervention (SC or IV Route):

Discontinuation: leukopenia, thrombocytopenia, neutropenia.

Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia.

Dose Reduced: leukopenia, neutropenia, thrombocytopenia.

Adverse Reactions In Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to Ladakamycin in 443 MDS patients from 4 clinical studies. Study 1 was a supportive-care controlled trial (SC administration), Studies 2 and 3 were single arm studies (one with SC administration and one with IV administration), and Study 4 was an international randomized trial (SC administration).

In Studies 1, 2 and 3, a total of 268 patients were exposed to Ladakamycin, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately one year). Ladakamycin was studied primarily in supportive-care controlled and uncontrolled trials (n=150 and n=118, respectively). The population in the subcutaneous studies (n=220) was 23 to 92 years old (mean 66.4 years), 68% male, and 94% white, and had MDS or AML. The population in the IV study (n=48) was 35 to 81 years old (mean 63.1 years), 65% male, and 100% white. Most patients received average daily doses between 50 and 100 mg/m².

In Study 4, a total of 175 patients with higher-risk MDS (primarily RAEB and RAEB-T subtypes) were exposed to Ladakamycin. Of these patients, 119 were exposed for 6 or more cycles, and 63 for at least 12 cycles. The mean age of this population was 68.1 years (ranging from 42 to 83 years), 74% were male, and 99% were white. Most patients received daily Ladakamycin doses of 75 mg/m².

Table 1 presents adverse reactions occurring in at least 5% of patients treated with Ladakamycin (SC) in Studies 1 and 2. It is important to note that duration of exposure was longer for the Ladakamycin-treated group than for the observation group: patients received Ladakamycin for a mean of 11.4 months while mean time in the observation arm was 6.1 months.

Table 1: Most Frequently Observed Adverse Reactions ( ≥ 5.0% in All SC Ladakamycin Treated Patients; Studies 1 and 2)

In Studies 1, 2 and 4 with SC administration of Ladakamycin, adverse reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and injection site erythema/reaction tended to increase in incidence with higher doses of Ladakamycin. Adverse reactions that tended to be more pronounced during the first 1 to 2 cycles of SC treatment compared with later cycles included thrombocytopenia, neutropenia, anemia, nausea, vomiting, injection site erythema/pain/bruising/reaction, constipation, petechiae, dizziness, anxiety, hypokalemia, and insomnia. There did not appear to be any adverse reactions that increased in frequency over the course of treatment.

Overall, adverse reactions were qualitatively similar between the IV and SC studies. Adverse reactions that appeared to be specifically associated with the IV route of administration included infusion site reactions (e.g. erythema or pain) and catheter site reactions (e.g. infection, erythema, or hemorrhage).

In clinical studies of either SC or IV Ladakamycin, the following serious adverse reactions occurring at a rate of < 5% (and not described in Tables 1 or 2) were reported:

Blood and lymphatic system disorders: agranulocytosis, bone marrow failure, pancytopenia splenomegaly.

Cardiac disorders: atrial fibrillation, cardiac failure, cardiac failure congestive, cardiorespiratory arrest, congestive cardiomyopathy.

Eye disorders: eye hemorrhage

Gastrointestinal disorders: diverticulitis, gastrointestinal hemorrhage, melena, perirectal abscess.

General disorders and administration site conditions: catheter site hemorrhage, general physical health deterioration, systemic inflammatory response syndrome.

Hepatobiliary disorders: cholecystitis.

Immune system disorders: anaphylactic shock, hypersensitivity.

Infections and infestations: abscess limb, bacterial infection, cellulitis, blastomycosis, injection site infection, Klebsiella sepsis, neutropenic sepsis, pharyngitis streptococcal, pneumonia Klebsiella, sepsis, septic shock, Staphylococcal bacteremia, Staphylococcal infection, toxoplasmosis.

Metabolism and nutrition disorders: dehydration.

Musculoskeletal and connective tissue disorders: bone pain aggravated, muscle weakness, neck pain.

Neoplasms benign, malignant and unspecified: leukemia cutis.

Nervous system disorders: cerebral hemorrhage, convulsions, intracranial hemorrhage.

Renal and urinary disorders: loin pain, renal failure.

Respiratory, thoracic and mediastinal disorders: hemoptysis, lung infiltration, pneumonitis, respiratory distress.

Skin and subcutaneous tissue disorders: pyoderma gangrenosum, rash pruritic, skin induration.

Surgical and medical procedures: cholecystectomy.

Vascular disorders: orthostatic hypotension.

Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of Ladakamycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Interstitial lung disease
• Tumor lysis syndrome
• Injection site necrosis
• Sweet's syndrome (acute febrile neutrophilic dermatosis)
• Necrotizing fasciitis (including fatal cases)

A pyrimidine nucleoside analogue that inhibits DNA methyltransferase, impairing DNA methylation. It is also an antimetabolite of cytidine, incorporated primarily into RNA. Azacytidine has been used as an antineoplastic agent. [PubChem]