Ninlaro 4mg

Ninlaro 4mg a second generation proteasome inhibitor (PI) and the first oral PI approved by the FDA in November 2015 for multiple myeloma treatment in combination with 2 other therapies (lenalidomide and dexamethasone) for patients who have received at least 1 prior therapy. It was found to have similar efficacy to bortezomib (the first PI approved for multiple myeloma therapy) in the control of myeloma growth and prevention of bone loss. Ninlaro 4mg citrate is marketed by Takeda Pharmaceuticals under the brand name Ninlaro 4mg, which is a prodrug that becomes quickly converted to its active metabolite, Ninlaro 4mg, after administration.

Ninlaro 4mg is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. (multiple myeloma;)

Ninlaro 4mg is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Ninlaro 4mg is used in combination chemotherapy to treat multiple myeloma (bone marrow cancer). Ninlaro 4mg is given together with lenalidomide and a steroid medicine called dexamethasone.

Ninlaro 4mg is usually given after at least one other cancer medicine has been tried without success.

Ninlaro 4mg may also be used for purposes not listed in this medication guide.

Dosing and Administration Guidelines

Ninlaro 4mg in combination with lenalidomide and dexamethasone

The recommended starting dose of Ninlaro 4mg is 4 mg administered orally once a week on Days 1, 8, and 15 of a 28-day treatment cycle.

The recommended starting dose of lenalidomide is 25 mg administered daily on Days 1 through 21 of a 28-day treatment cycle.

The recommended starting dose of dexamethasone is 40 mg administered on Days 1, 8, 15, and 22 of a 28-day treatment cycle.

For additional information regarding lenalidomide and dexamethasone, refer to their prescribing information.

Ninlaro 4mg should be taken once a week on the same day and at approximately the same time for the first three weeks of a four week cycle. Ninlaro 4mg should be taken at least one hour before or at least two hours after food. The whole capsule should be swallowed with water. The capsule should not be crushed, chewed or opened.

If a Ninlaro 4mg dose is delayed or missed, the dose should be taken only if the next scheduled dose is ≥ 72 hours away. A missed dose should not be taken within 72 hours of the next scheduled dose. A double dose should not be taken to make up for the missed dose.

If vomiting occurs after taking a dose, the patient should not repeat the dose. The patient should resume dosing at the time of the next scheduled dose.

Prior to initiating a new cycle of therapy:

• Absolute neutrophil count should be at least 1,000/mm3
• Platelet count should be at least 75,000/mm3
• Non-hematologic toxicities should, at the physician's discretion, generally be recovered to patient's baseline condition or Grade 1 or lower

Treatment should be continued until disease progression or unacceptable toxicity.

Dose Modification Guidelines

The Ninlaro 4mg dose reduction steps are presented in Table 2 and the dose modification guidelines are provided in Table 3.

An alternating dose modification approach is recommended for Ninlaro 4mg and lenalidomide for thrombocytopenia, neutropenia, and rash as described in Table 3. Refer to the lenalidomide prescribing information if dose reduction is needed for lenalidomide.

Dosage in Patients with Hepatic Impairment

Reduce the starting dose of Ninlaro 4mg to 3 mg in patients with moderate (total bilirubin greater than 1.5-3 × ULN) or severe (total bilirubin greater than 3 × ULN) hepatic impairment.

Dosage in Patients with Renal Impairment

Reduce the starting dose of Ninlaro 4mg to 3 mg in patients with severe renal impairment (creatinine clearance less than 30 mL/min) or end-stage renal disease (ESRD) requiring dialysis. Ninlaro 4mg is not dialyzable and therefore can be administered without regard to the timing of dialysis.

Refer to the lenalidomide prescribing information for dosing recommendations in patients with renal impairment.

See also:
What is the most important information I should know about Ninlaro 4mg?

There are no contraindications listed in the manufacturer's labeling.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to Ninlaro 4mg or any component of the formulation

Use: Labeled Indications

Multiple myeloma: Treatment of multiple myeloma (in combination with lenalidomide and dexamethasone) in patients who have received at least one prior therapy

See also:
What other drugs will affect Ninlaro 4mg?

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Ninlaro 4mg. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Estrogen Derivatives (Contraceptive): Ninlaro 4mg may decrease the serum concentration of Estrogen Derivatives (Contraceptive). More specifically, use of Ninlaro 4mg with dexamethasone may decrease the serum concentrations of estrogen derivative contraceptives. Management: Patients of childbearing potential should use a nonhormonal barrier contraceptive during and 90 days following Ninlaro 4mg treatment. Consider therapy modification

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Progestins (Contraceptive): Ninlaro 4mg may decrease the serum concentration of Progestins (Contraceptive). More specifically, use of Ninlaro 4mg with dexamethasone may decrease the serum concentrations of contraceptive progestins. Management: Patients of childbearing potential should use a nonhormonal barrier contraceptive during and 90 days following Ninlaro 4mg treatment. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

St John's Wort: May decrease the serum concentration of Ninlaro 4mg. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

See also:
What are the possible side effects of Ninlaro 4mg?

The following adverse reactions are described in detail in other sections of the prescribing information:

• Thrombocytopenia
• Gastrointestinal Toxicities
• Peripheral Neuropathy
• Peripheral Edema
• Cutaneous Reactions
• Hepatotoxicity

Clinical Trials Experience

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 safety population from the randomized, double-blind, placebo-controlled clinical study included 720 patients with relapsed and/or refractory multiple myeloma, who received Ninlaro 4mg in combination with lenalidomide and dexamethasone (Ninlaro 4mg regimen; N=360) or placebo in combination with lenalidomide and dexamethasone (placebo regimen; N=360).

The most frequently reported adverse reactions (≥ 20%) in the Ninlaro 4mg regimen and greater than the placebo regimen were diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting, and back pain. Serious adverse reactions reported in ≥ 2% of patients included thrombocytopenia (2%) and diarrhea (2%). For each adverse reaction, one or more of the three drugs was discontinued in < 1% of patients in the Ninlaro 4mg regimen.

Table 4 summarizes the adverse reactions occurring in at least 5% of patients with at least a 5% difference between the Ninlaro 4mg regimen and the placebo regimen.

Table 4: Non-Hematologic Adverse Reactions Occurring in ≥ 5% of Patients with a ≥ 5% Difference Between the Ninlaro 4mg Regimen and the Placebo Regimen (All Grades, Grade 3 and Grade 4)

Table 5 represents pooled information from adverse event and laboratory data.

Table 5: Thrombocytopenia and Neutropenia

Eye Disorders

Eye disorders were reported with many different preferred terms but in aggregate, the frequency was 26% in patients in the Ninlaro 4mg regimen and 16% of patients in the placebo regimen. The most common adverse reactions were blurred vision (6% in the Ninlaro 4mg regimen and 3% in the placebo regimen), dry eye (5% in the Ninlaro 4mg regimen and 1% in the placebo regimen), and conjunctivitis (6% in the Ninlaro 4mg regimen and 1% in the placebo regimen). Grade 3 adverse reactions were reported in 2% of patients in the Ninlaro 4mg regimen and 1% in the placebo regimen.

Adverse Reactions Reported Outside of the Randomized Controlled Trial

The following serious adverse reactions have each been reported at a frequency of < 1%: acute febrile neutrophilic dermatosis (Sweet's syndrome), Stevens-Johnson syndrome, transverse myelitis, posterior reversible encephalopathy syndrome, tumor lysis syndrome, and thrombotic thrombocytopenic purpura.