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  2.1     Recommended Dosing

  The recommended starting dose of FARYDAK is 20 mg, taken orally once every other day for 3 doses per week in Weeks 1 and 2 of each 21-day cycle for up to 8 cycles. Consider continuing treatment for an additional 8 cycles for patients with clinical benefit who do not experience unresolved severe or medically significant toxicity. The total duration of treatment may be up to 16 cycles (48 weeks). FARYDAK is administered in combination with bortezomib and dexamethasone as shown in Table 1 and Table 2.

  The recommended dose of bortezomib is 1.3 mg/m2 given as an injection. The recommended dose of dexamethasone is 20 mg taken orally per scheduled day, on a full stomach.

  Table 1: Recommended Dosing Schedule of FARYDAK in Combination with Bortezomib and Dexamethasone During Cycles 1 to 8 21-Day Cycle Cycles 1 to 8
  (3-Week cycles) Week 1
  Days Week 2
  Days Week 3 FARYDAK 1 3 5 8 10 12 Rest period Bortezomib 1 4 8 11 Rest period Dexamethasone 1 2 4 5 8 9 11 12 Rest period Table 2: Recommended Dosing Schedule of FARYDAK in Combination with Bortezomib and Dexamethasone During Cycles 9 to 16 21-Day Cycle Cycles 9 to 16
  (3-Week cycles) Week 1
  Days Week 2
  Days Week 3 FARYDAK 1 3 5 8 10 12 Rest period Bortezomib 1 8 Rest period Dexamethasone 1 2 8 9 Rest period 2.2     Administration and Monitoring Instructions

  FARYDAK should be taken orally once on each scheduled day at about the same time, either with or without food [see Clinical Pharmacology (12.3)].

  FARYDAK capsules should be swallowed whole with a cup of water. Do not open, crush, or chew the capsules [see How Supplied/Storage and Handling (16)].

  If a dose is missed it can be taken up to 12 hours after the specified dose time. If vomiting occurs the patient should not repeat the dose, but should take the next usual scheduled dose.

  Counsel patients on the correct dosing schedule, technique of administration of FARYDAK, and when to take FARYDAK if dosing adjustments are made.

  Prior to the start of FARYDAK treatment and during treatment, monitoring should include:

  Complete Blood Count (CBC): Obtain a CBC before initiating treatment. Verify that the baseline platelet count is at least 100 x 109/L and the baseline absolute neutrophil count (ANC) is at least 1.5 x 109/L. Monitor the CBC weekly (or more often as clinically indicated) during treatment. [see Warnings and Precautions (5.4) Adverse Reactions (6.1)]. ECG: Perform an ECG prior to the start of therapy and repeat periodically during treatment as clinically indicated. Verify that the QTcF is less than 450 msec prior to initiation of treatment with FARYDAK. If during treatment with FARYDAK, the QTcF increases to ≥480 msec, interrupt treatment. Correct any electrolyte abnormalities. If QT prolongation does not resolve, permanently discontinue treatment with FARYDAK [see Warnings and Precautions (5.2), Adverse Reactions (6.1)]. During the clinical trial, ECGs were performed at baseline and prior to initiation of each cycle for the first 8 cycles. Serum Electrolytes: Obtain electrolytes, including potassium and magnesium, at baseline and monitor during therapy. Correct abnormal electrolyte values before treatment [see Warnings and Precautions (5.2), Adverse Reactions (6.1)]. During the trial, monitoring was conducted prior to the start of each cycle, at Day 11 of cycles 1 to 8, and at the start of each cycle for cycles 9 to 16.

  For additional information please refer to the bortezomib and dexamethasone prescribing information.

  2.3     Dose Adjustments and Modifications for Toxicity

  Dose and/or schedule modification of FARYDAK may be required based on toxicity. Management of adverse drug reactions may require treatment interruption and/or dose reductions. If dose reduction is required, the dose of FARYDAK should be reduced in increments of 5 mg (i.e., from 20 mg to 15 mg, or from 15 mg to 10 mg). If the dosing of FARYDAK is reduced below 10 mg given 3 times per week, discontinue FARYDAK. Keep the same treatment schedule (3-week treatment cycle) when reducing dose. The table also lists Bortezomib (BTZ) dose modification procedures from the clinical trials.

  Table 3: Dose Modifications for Most Common Toxicities BTZ = bortezomib
  ANC = absolute neutrophil count
  Hb = hemoglobin
  IV = intravenous Thrombocytopenia Platelets <50 x 109/L
  
  CTCAE Grade 3 Platelets <50 x 109/L
  with bleeding
  CTCAE Grade 3 Platelets <25 x 109/L
  
  CTCAE Grade 4 Maintain FARYDAK dose.
  Monitor platelet counts at least weekly. Interrupt FARYDAK.
  Monitor platelet counts
  at least weekly until
  ≥50 x 109/L,
  then restart at reduced dose Interrupt FARYDAK.
  Monitor platelet counts
  at least weekly until
  ≥50 x 109/L,
  then restart at reduced dose Maintain BTZ dose - Interrupt BTZ until thrombocytopenia resolves to ≥ 75 x 109/L
  - If only 1 dose was omitted prior to correction to these levels, restart BTZ at same dose
  - If 2 or more doses were omitted consecutively, or within the same cycle, BTZ should be restarted at a reduced dose Neutropenia ANC 0.75 to 1.0 x 109/L
  CTCAE Grade 3 ANC 0.5 to 0.75 x 109/L
  CTCAE Grade 3
  (2 or more occurrences) ANC <1.0 x 109/L
  (CTCAE Grade 3)
  with febrile Neutropenia
  (any grade) ANC <0.5 x 109/L
  CTCAE Grade 4 Maintain FARYDAK dose. Interrupt FARYDAK until ANC ≥1.0 x 109/L,
  then restart at same dose Interrupt FARYDAK until
  febrile neutropenia resolves and
  ANC ≥1.0 x 109/L,
  then restart at reduced dose Interrupt FARYDAK until
  ANC ≥1.0 x 109/L,
  then restart at reduced dose Maintain BTZ dose - Interrupt BTZ until febrile neutropenia resolves and ANC ≥1.0 x 109/L
  - If only 1 dose was omitted prior to correction to these levels, restart BTZ at same dose
  - If 2 or more doses were omitted consecutively, or within the same cycle, BTZ should be restarted at a reduced dose Anemia Hb <8 g/dL
  CTCAE Grade 3 Interrupt FARYDAK until Hb ≥10 g/dL
  Restart at reduced dose. Diarrhea Moderate Diarrhea
  4 to 6 stools/day
  
  CTCAE Grade 2 Severe Diarrhea
  (≥7 stools/day)
  IV fluids or hospitalization required
  CTCAE Grade 3 Life-threatening Diarrhea
  
  
  CTCAE Grade 4 Interrupt FARYDAK until resolved.
  Restart at same dose. Interrupt FARYDAK until resolved.
  Restart at reduced dose. Permanently discontinue FARYDAK Consider Interruption of BTZ until resolved.
  Restart at same dose. Interrupt BTZ until resolved.
  Restart at reduced dose. Permanently discontinue BTZ Nausea or Vomiting Severe Nausea
  CTCAE Grade 3/4 Severe / Life-threatening Vomiting
  CTCAE Grade 3/4 Interrupt FARYDAK until resolved,
  then restart at reduced dose. Interrupt FARYDAK until resolved,
  then restart at reduced dose.

  Myelosuppression

  Interrupt or reduce the dose of FARYDAK in patients who have thrombocytopenia, neutropenia or anemia according to instructions in Table 3. For patients with severe thrombocytopenia, consider platelet transfusions [see Warnings and Precautions (5.4), Adverse Reactions (6.1)]. Discontinue FARYDAK treatment if thrombocytopenia does not improve despite the recommended treatment modifications or if repeated platelet transfusions are required.

  In the event of Grade 3 or 4 neutropenia, consider dose reduction and/or the use of growth factors (e.g., G-CSF). Discontinue FARYDAK if neutropenia does not improve despite dose modifications, colony-stimulating factors, or in case of severe infection.

  Gastrointestinal Toxicity

  Gastrointestinal toxicity is common in patients treated with FARYDAK. Patients who experience diarrhea, nausea, or vomiting may require treatment interruption or dose reduction (Table 3). At the first sign of abdominal cramping, loose stools, or onset of diarrhea, patients should be treated with anti-diarrheal medication (e.g., loperamide). Consider and administer prophylactic anti-emetics as clinically indicated.

  Other Adverse Drug Reactions

  For patients experiencing Grade 3/4 adverse drug reactions other than thrombocytopenia, neutropenia, or gastrointestinal toxicity, the recommendation is the following:

  CTC Grade 2 toxicity recurrence and CTC Grade 3 and 4 - omit the dose until recovery to CTC Grade 1 or less and restart treatment at a reduced dose CTC Grade 3 or 4 toxicity recurrence, a further dose reduction may be considered once the adverse events have resolved to CTC Grade 1 or less. 2.4     Dose Modifications for Use in Hepatic Impairment

  Reduce the starting dose of FARYDAK to 15 mg in patients with mild hepatic impairment and 10 mg in patients with moderate hepatic impairment. Avoid use in patients with severe hepatic impairment. Monitor patients frequently for adverse events and adjust dose as needed for toxicity [see Dosing and Administration (2.2), Warnings and Precautions (5.6), Hepatic Impairment (8.6), Clinical Pharmacology (12.3)].

  2.5     Dose Modifications for Use with Strong CYP3A Inhibitors

  Reduce the starting dose of FARYDAK to 10 mg when coadministered with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir) [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

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