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Uses, Dosage, Side Effects, Interactions, Warning

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Myelosuppression

In uncontrolled trials with SYNRIBO, patients with
chronic phase and accelerated phase CML experienced NCI CTC (version 3.0) Grade
3 or 4 thrombocytopenia (85%, 88%), neutropenia (81%, 71%), and anemia (62%,
80%), respectively. Fatalities related to myelosuppression occurred in 3% of
patients in the safety population (N=163). Patients with neutropenia are at
increased risk for infections, and should be monitored frequently and advised
to contact a physician if they have symptoms of infection or fever.

Monitor complete blood counts weekly during induction and
initial maintenance cycles and every two weeks during later maintenance cycles,
as clinically indicated. In clinical trials myelosuppression was generally
reversible and usually managed by delaying next cycle and/or reducing days of
treatment with SYNRIBO [see DOSAGE AND ADMINISTRATION and ADVERSE
REACTIONS
].

Bleeding

SYNRIBO causes severe thrombocytopenia which increases
the risk of hemorrhage. In clinical trials with CP and AP CML patients, a high
incidence of Grade 3 and 4 thrombocytopenia (85% and 88%, respectively) was
observed. Fatalities from cerebral hemorrhage occurred in 2% of patients
treated with SYNRIBO in the safety population. Severe, non-fatal,
gastrointestinal hemorrhages occurred in 2% of patients in the same population.
Most bleeding events were associated with severe thrombocytopenia.

Monitor platelet counts as part of the CBC monitoring as
recommended [see Myelosuppression]. Avoid anticoagulants,
aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) when the platelet
count is less than 50,000/μL as they may increase the risk of bleeding.

Hyperglycemia

SYNRIBO can induce glucose intolerance. Grade 3 or 4
hyperglycemia was reported in 11% of patients in the safety population.
Hyperosmolar non-ketotic hyperglycemia occurred in 1 patient treated with
SYNRIBO in the safety population. Monitor blood glucose levels frequently, especially
in patients with diabetes or risk factors for diabetes. Avoid SYNRIBO in
patients with poorly controlled diabetes mellitus until good glycemic control
has been established.

Embryo-Fetal Toxicity

Based on findings from animal reproduction studies and
the drug’s mechanism of action, SYNRIBO can cause fetal harm when administered
to a pregnant woman. Advise pregnant women of the potential risk to a fetus.
Advise females of reproductive potential to use an effective method of
contraception during treatment with SYNRIBO and for 6 months after the final
dose [see Use In Specific Populations and CLINICAL PHARMACOLOGY].

Advise males with female partners of reproductive
potential to use effective contraception during treatment with SYNRIBO and for
3 months after the final dose [see Use In Specific Populations].

Patient Counseling Information

Availability Of Medication Guide And Instructions For Use

Advise the patient and/or caregiver to read the
FDA-approved patient labeling (Medication Guide and Instructions for Use).
Assist patients and caregivers in understanding their contents and give them
the opportunity to discuss the contents of the Medication Guide and
Instructions for Use and to obtain answers to any questions they may have prior
to initiating therapy. The complete text of the Medication Guide and
Instructions for Use are attached to the prescribing information.

Patient Training

Once it is determined that a patient is an appropriate
candidate for self-administration or administration by a caregiver, ensure that
patients receive the necessary supplies for home administration of SYNRIBO and
train them on the following [see DOSAGE AND ADMINISTRATION]:

  • How to transport reconstituted SYNRIBO in a secure
    container or packaging and under recommended temperature conditions
  • Acceptable storage conditions and use times for
    reconstituted SYNRIBO

    • When stored in a refrigerator (2°C to 8°C [36°F to
      46°F]), use within 6 days (144 hours)
    • When stored at room temperature (not to exceed 25°C
      [77°F]), use within 12 hours
  • If stored in a refrigerator, keep SYNRIBO from coming
    into contact with food or drink.
  • To wear disposable gloves and protective eyewear when
    handling SYNRIBO.
  • To wash hands before putting on gloves and after removing
    gloves.
  • Not to eat or drink while handling SYNRIBO. To administer
    SYNRIBO in an area away from food or food preparation areas.
  • To administer SYNRIBO in a location away from children
    and pregnant women.
  • Proper subcutaneous injection technique including
    acceptable sites.
  • The importance of body site selection for administering
    the injection, as well as the importance of alternating the injection sites.
    Advise patients to not inject SYNRIBO into areas of the skin that are tender,
    red, bruised, hard, or that have scars or stretch marks.
  • In the case of a missed dose: If a patient misses an
    injection, skip the missed dose and the patient should give the next scheduled
    injection at the next scheduled time. Inform patients NOT to give two
    injections to make up for a missed injection.
  • In the case that SYNRIBO comes into contact with a
    patient’s skin or eyes: Advise patients to wash exposed skin with soap and water
    and in the case of eye exposure, thoroughly flush the eye with water. After
    washing or flushing, advise patients to call their healthcare provider
    immediately.
  • In the case that too much SYNRIBO is injected or that
    SYNRIBO is accidentally swallowed: Instruct patients to contact their
    healthcare provider immediately if they have injected too much SYNRIBO, or if
    someone has swallowed SYNRIBO.
  • Disposal procedures, including use of an appropriate
    biohazard container and return of the container to the clinic or pharmacy for
    final disposal. Inform patients NOT to recap or clip the used needle and not to
    place used needles, syringes, vials, and other used supplies in a household
    trash or recycle container.
  • Accidental spillage procedures, including wiping the spilled
    liquid with the absorbent pad (using protective eyewear and gloves), washing
    the area with water and soap, and proper disposal of materials.
Myelosuppression

Advise patients of the likelihood that SYNRIBO will cause
a decrease in white blood cells, platelets, and red blood cells and that
monitoring of these parameters will be needed. Instruct patients to contact a
health care professional if they develop a fever, or other signs/symptoms of
infection; shortness of breath, significant fatigue, or bleeding [see WARNINGS
AND PRECAUTIONS
].

Bleeding

Advise patients of the possibility of serious bleeding
due to low platelet counts. Instruct patients to report immediately any signs
or symptoms suggestive of hemorrhage (unusual bleeding, easy bruising or blood
in urine or stool; confusion, slurred speech, or altered vision). Instruct
patients to report in advance if they plan to have any dental or surgical
procedures [see WARNINGS AND PRECAUTIONS].

Hyperglycemia

Advise patients with diabetes of the possibility of
hyperglycemia and the need for careful monitoring of blood glucose levels.
Patients with poorly controlled diabetes mellitus should not be treated with
omacetaxine mepesuccinate until good glycemic control has been established [see
WARNINGS AND PRECAUTIONS
].

Gastrointestinal Distress

Advise patients that they may experience nausea,
diarrhea, abdominal pain, constipation, and vomiting. If these symptoms
persist, they should seek medical attention.

Fatigue

Advise patients that SYNRIBO may cause tiredness and to
avoid driving any vehicle or operating any dangerous tools or machinery if they
experience this side effect.

Rash

Advise patients that they may experience skin rash.
Advise patients to immediately report severe or worsening rash or itching.

Alopecia

Advise patients that they may experience hair loss.

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive
potential of the potential risk to a fetus. Advise females to inform their
healthcare provider of a known or suspected pregnancy [see WARNINGS AND
PRECAUTIONS
and Use In Specific Populations]. Advise female patients
of reproductive potential to use effective contraception during treatment with
SYNRIBO and for 6 months after the final dose [see Use In Specific
Populations
].

Advise males with female partners of reproductive
potential to use effective contraception during treatment with SYNRIBO and for
3 months after the final dose [see Use In Specific Populations and Nonclinical
Toxicology
].

Lactation

Advise females not to breastfeed during treatment with
SYNRIBO and for 2 weeks after the final dose [see Use In Specific
Populations
].

Infertility

Advise males of reproductive potential that SYNRIBO may
impair fertility [see Use In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No carcinogenicity studies have been conducted with
omacetaxine mepesuccinate.

Omacetaxine mepesuccinate was genotoxic in an in vitro
chromosomal aberration test system in Chinese hamster ovary (CHO) cells, but
was not mutagenic when tested in an in vitro bacterial cell assay (Ames test),
and it did not induce genetic damage using an in vivo mouse micronucleus assay.

SYNRIBO may impair male fertility. Studies in mice
demonstrated adverse effects on male reproductive organs. Bilateral
degeneration of the seminiferous tubular epithelium in testes and
hypospermia/aspermia in the epididymides were reported in the highest dose
group (2.33 mg/kg/day reduced to 1.67 mg/kg/day; 7 to 5 mg/m²/day) following
subcutaneous injection of omacetaxine mepesuccinate for six cycles over six
months. The doses used in the mice were approximately two to three times the
recommended daily human dose based on body surface area.

Use In Specific Populations

Pregnancy

Risk Summary

Based on its mechanism of action and findings from animal
studies, SYNRIBO can cause fetal harm when administered to pregnant women. In
animal reproduction studies, subcutaneous administration of omacetaxine
mepesuccinate to pregnant mice during organogenesis at doses approximately
0.25-0.5 times the maximum recommended human doses (MRHD) resulted in
embryo-fetal mortality, structural abnormalities, and alterations to growth (see
Data). There are no available data on SYNRIBO use in pregnant women to
evaluate for a drug-associated risk of major birth defects, miscarriage or
adverse maternal or fetal outcomes. Advise pregnant women of the potential risk
to a fetus [see WARNINGS AND PRECAUTIONS].

The estimated background risk of major birth defects and
miscarriage for the indicated population is unknown. All pregnancies have a
background risk of birth defect, loss, or other adverse outcomes. In the U.S.
general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
respectively.

Data

Animal Data

In an embryo-fetal development study, pregnant mice were
administered omacetaxine mepesuccinate subcutaneously during the period of
organogenesis at doses of 0.63 or 1.23 mg/m²/day (approximately 0.25-0.5 times
the MRHD on a body surface area basis). Drug-related adverse effects included
embryonic death, an increase in unossified bones/reduced bone ossification, and
decreased fetal body weights. Fetal toxicity occurred at doses of 1.23 mg/m²/day,
which is approximately half the recommended daily human dose.

Lactation

Risk Summary

There are no data on the presence of omacetaxine
mepesuccinate in either human or animal milk, the effects on the breastfed
child, or the effects on milk production. Because of the potential for serious
adverse reactions in the breastfed child, advise patients that breastfeeding is
not recommended during treatment with SYNRIBO, and for 2 weeks after the final
dose.

Females And Males Of Reproductive Potential

Pregnancy Testing

Pregnancy testing is recommended for females of
reproductive potential prior to initiating SYNRIBO.

Contraception

Females

SYNRIBO can cause embryo-fetal harm when administered to
pregnant women [see Use In Specific Populations]. Advise female patients
of reproductive potential to use effective contraception during treatment with
SYNRIBO and for 6 months after the final dose.

Males

Based on genotoxicity findings, advise males with female
partners of reproductive potential to use effective contraception during
treatment with SYNRIBO and for 3 months after the final dose [see Nonclinical
Toxicology
].

Infertility

Males

Based on findings from animal studies, SYNRIBO may impair
male fertility. Studies in mice demonstrated adverse effects on male
reproductive organs where bilateral degeneration of the seminiferous tubular
epithelium in testes and hypospermia/aspermia were observed [see Nonclinical
Toxicology
]. The long-term effects of SYNRIBO on male fertility, including
the reversibility of adverse effects, have not been studied.

Pediatric Use

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

Geriatric Use

In the chronic and accelerated phase CML efficacy
populations 23 (30%) and 16 (46%) patients were ≥65 years of age. For the
age subgroups of <65 years of age and ≥65 years of age, there were
differences between the subgroups, with higher rates of major cytogenetic
responses (MCyRs) in younger patients with CP CML compared with older patients
(23% vs. 9%, respectively) and higher rates of major hematologic responses
(MaHRs) in older patients with AP CML compared with younger patients (31% vs.
0%, respectively). Patients ≥65 years of age were more likely to
experience toxicity, most notably hematologic toxicity.

Effect Of Gender

Of the 76 patients included in the chronic phase CML
population efficacy analysis, 47 (62%) of the patients were men and 29 (38%)
were women. For patients with chronic phase CML, the MCyR rate in men was
higher than in women (21% vs. 14%, respectively). There were differences noted
in the safety profile of omacetaxine mepesuccinate in men and women with
chronic phase CML although the small number of patients in each group prevents
a definitive assessment. There were inadequate patient numbers in the accelerated
phase subset to draw conclusions regarding a gender effect on efficacy.

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