JAKAFI (Page 5 of 12)
5.2 Risk of Infection
Serious bacterial, mycobacterial, fungal and viral infections have occurred [ see Adverse Reactions ( 6.1)]. Delay starting therapy with Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly. Use active surveillance and prophylactic antibiotics according to clinical guidelines.
Tuberculosis
Tuberculosis infection has been reported in patients receiving Jakafi. Observe patients receiving Jakafi for signs and symptoms of active tuberculosis and manage promptly.
Prior to initiating Jakafi, patients should be evaluated for tuberculosis risk factors, and those at higher risk should be tested for latent infection. Risk factors include, but are not limited to, prior residence in or travel to countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, and a history of active or latent tuberculosis where an adequate course of treatment cannot be confirmed.
For patients with evidence of active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis before starting Jakafi. The decision to continue Jakafi during treatment of active tuberculosis should be based on the overall risk-benefit determination.
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) has occurred with Jakafi treatment. If PML is suspected, stop Jakafi and evaluate.
Herpes Zoster and Herpes Simplex
Herpes zoster infection has been reported in patients receiving Jakafi [see Adverse Reactions (6.1)]. Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected.
Herpes simplex virus reactivation and/or dissemination has been reported in patients receiving Jakafi [see Adverse Reactions (6.2)]. Monitor patients for the development of herpes simplex infections. If a patient develops evidence of dissemination of herpes simplex, consider interrupting treatment with Jakafi; patients should be promptly treated and monitored according to clinical guidelines.
Hepatitis B
Hepatitis B viral load (HBV-DNA titer) increases, with or without associated elevations in alanine aminotransferase and aspartate aminotransferase, have been reported in patients with chronic HBV infections taking Jakafi. The effect of Jakafi on viral replication in patients with chronic HBV infection is unknown. Patients with chronic HBV infection should be treated and monitored according to clinical guidelines.
5.3 Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi
Following discontinuation of Jakafi, symptoms from myeloproliferative neoplasms may return to pretreatment levels over a period of approximately one week. Some patients with MF have experienced one or more of the following adverse events after discontinuing Jakafi: fever, respiratory distress, hypotension, DIC, or multi-organ failure. If one or more of these occur after discontinuation of, or while tapering the dose of Jakafi, evaluate for and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi therapy without consulting their physician. When discontinuing or interrupting therapy with Jakafi for reasons other than thrombocytopenia or neutropenia [see Dosage and Administration (2.8)] , consider tapering the dose of Jakafi gradually rather than discontinuing abruptly.
5.4 Non-Melanoma Skin Cancer (NMSC)
Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred in patients treated with Jakafi. Perform periodic skin examinations.
5.5 Lipid Elevations
Treatment with Jakafi has been associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides [see Adverse Reactions ( 6.1)]. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined in patients treated with Jakafi. Assess lipid parameters approximately 8-12 weeks following initiation of Jakafi therapy. Monitor and treat according to clinical guidelines for the management of hyperlipidemia.
5.6 Major Adverse Cardiovascular Events (MACE)
Another JAK-inhibitor has increased the risk of MACE, including cardiovascular death, myocardial infarction, and stroke (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which Jakafi is not indicated.
Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Jakafi particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur.
5.7 Thrombosis
Another JAK-inhibitor has increased the risk of thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which Jakafi is not indicated. In patients with MF and PV treated with Jakafi in clinical trials, the rates of thromboembolic events were similar in Jakafi and control treated patients.
Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately.
5.8 Secondary Malignancies
Another JAK-inhibitor has increased the risk of lymphoma and other malignancies excluding NMSC (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which Jakafi is not indicated. Patients who are current or past smokers are at additional increased risk.
Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Jakafi, particularly in patients with a known secondary malignancy (other than a successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers.
6. ADVERSE REACTIONS
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
- Thrombocytopenia, Anemia and Neutropenia [see Warnings and Precautions (5.1)]
- Risk of Infection [see Warnings and Precautions (5.2)]
- Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi [see Warnings and Precautions (5.3)]
- Non-Melanoma Skin Cancer [see Warnings and Precautions (5.4)]
- Lipid Elevations [ see Warnings and Precautions ( 5.5)]
- Major Adverse Cardiovascular Events (MACE) [ see Warnings and Precautions ( 5.6)]
- Thrombosis [ see Warnings and Precautions ( 5.7)]
- Secondary Malignancies [ see Warnings and Precautions ( 5.8)]
6.1 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.
Myelofibrosis
The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with MF in two Phase 3 studies.
In these two Phase 3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 89% of patients treated for more than 6 months and 25% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 x 109 /L) and 20 mg twice daily (pretreatment platelet counts greater than 200 x 109 /L), 65% and 25% of patients, respectively, required a dose reduction below the starting dose within the first 8 weeks of therapy.
In a double-blind, randomized, placebo-controlled study of Jakafi, among the 155 patients treated with Jakafi, the most frequent adverse reactions were thrombocytopenia and anemia [see Table 13]. Thrombocytopenia, anemia and neutropenia are dose-related effects. The three most frequent nonhematologic adverse reactions were bruising, dizziness and headache [see Table 12].
Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with Jakafi and 11% of patients treated with placebo.
Table 12 presents the most common nonhematologic adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.
| ||||||
| Jakafi(N=155) | Placebo(N=151) | |||||
| Adverse Reactions | AllGrades *(%) | Grade 3 (%) | Grade 4 (%) | AllGrades (%) | Grade 3 (%) | Grade 4 (%) |
| Bruising † | 23 | < 1 | 0 | 15 | 0 | 0 |
| Dizziness ‡ | 18 | < 1 | 0 | 7 | 0 | 0 |
| Headache | 15 | 0 | 0 | 5 | 0 | 0 |
| Urinary Tract Infections § | 9 | 0 | 0 | 5 | < 1 | < 1 |
| Weight Gain ¶ | 7 | < 1 | 0 | 1 | < 1 | 0 |
| Flatulence | 5 | 0 | 0 | < 1 | 0 | 0 |
| Herpes Zoster # | 2 | 0 | 0 | < 1 | 0 | 0 |
Description of Selected Adverse Reactions
Anemia
In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (< 1%) discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy.
In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients.
Thrombocytopenia
In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 x 109 /L was 14 days. Platelet transfusions were administered to 5% of patients receiving Jakafi and to 4% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in < 1% of patients receiving Jakafi and < 1% of patients receiving control regimens. Patients with a platelet count of 100 x 109 /L to 200 x 109 /L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 x 109 /L (17% versus 7%).
Neutropenia
In the two Phase 3 clinical studies, 1% of patients reduced or stopped Jakafi because of neutropenia.
Table 13 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.
| Jakafi(N=155) | Placebo(N=151) | |||||
| Laboratory Parameter | AllGrades †(%) | Grade 3 (%) | Grade 4 (%) | AllGrades (%) | Grade 3 (%) | Grade 4 (%) |
| Thrombocytopenia | 70 | 9 | 4 | 31 | 1 | 0 |
| Anemia | 96 | 34 | 11 | 87 | 16 | 3 |
| Neutropenia | 19 | 5 | 2 | 4 | < 1 | 1 |
Additional Data from the Placebo-Controlled Study
- 25% of patients treated with Jakafi and 7% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 2% for Jakafi with 1% Grade 3 and no Grade 4 ALT elevations.
- 17% of patients treated with Jakafi and 6% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was < 1% for Jakafi with no Grade 3 or 4 AST elevations.
- 17% of patients treated with Jakafi and < 1% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was < 1% for Jakafi with no Grade 3 or 4 cholesterol elevations.
Polycythemia Vera
In a randomized, open-label, active-controlled study, 110 patients with PV resistant to or intolerant of hydroxyurea received Jakafi and 111 patients received best available therapy [see Clinical Studies ( 14.2)]. The most frequent adverse reaction was anemia. Discontinuation for adverse events, regardless of causality, was observed in 4% of patients treated with Jakafi. Table 14 presents the most frequent nonhematologic adverse reactions occurring up to Week 32.
| ||||
| Jakafi(N=110) | Best Available Therapy(N=111) | |||
| Adverse Reactions | All Grades *(%) | Grade 3-4(%) | All Grades(%) | Grade 3-4(%) |
| Diarrhea | 15 | 0 | 7 | < 1 |
| Dizziness † | 15 | 0 | 13 | 0 |
| Dyspnea ‡ | 13 | 3 | 4 | 0 |
| Muscle Spasms | 12 | < 1 | 5 | 0 |
| Constipation | 8 | 0 | 3 | 0 |
| Herpes Zoster § | 6 | < 1 | 0 | 0 |
| Nausea | 6 | 0 | 4 | 0 |
| Weight Gain ¶ | 6 | 0 | < 1 | 0 |
| Urinary Tract Infections # | 6 | 0 | 3 | 0 |
| Hypertension | 5 | < 1 | 3 | < 1 |
Clinically relevant laboratory abnormalities are shown in Table 15.
| Jakafi(N=110) | Best Available Therapy(N=111) | |||||
| Laboratory Parameter | AllGrades †(%) | Grade 3(%) | Grade 4(%) | AllGrades(%) | Grade 3(%) | Grade 4(%) |
| Hematology | ||||||
| Anemia | 72 | < 1 | < 1 | 58 | 0 | 0 |
| Thrombocytopenia | 27 | 5 | < 1 | 24 | 3 | < 1 |
| Neutropenia | 3 | 0 | < 1 | 10 | < 1 | 0 |
| Chemistry | ||||||
| Hypercholesterolemia | 35 | 0 | 0 | 8 | 0 | 0 |
| Elevated ALT | 25 | < 1 | 0 | 16 | 0 | 0 |
| Elevated AST | 23 | 0 | 0 | 23 | < 1 | 0 |
| Hypertriglyceridemia | 15 | 0 | 0 | 13 | 0 | 0 |
Acute Graft-Versus-Host Disease
In a single-arm, open-label study, 71 adults (ages 18-73 years) were treated with Jakafi for aGVHD failing treatment with steroids with or without other immunosuppressive drugs [ see Clinical Studies ( 14.3)]. The median duration of treatment with Jakafi was 46 days (range, 4‑382 days).
There were no fatal adverse reactions to Jakafi. An adverse reaction resulting in treatment discontinuation occurred in 31% of patients. The most common adverse reaction leading to treatment discontinuation was infection (10%). Table 16 shows the adverse reactions other than laboratory abnormalities.
| Jakafi (N=71) | ||
| Adverse Reactions * | All Grades † (%) | Grade 3-4(%) |
| Infections (pathogen not specified) | 55 | 41 |
| Edema | 51 | 13 |
| Hemorrhage | 49 | 20 |
| Fatigue | 37 | 14 |
| Bacterial infections | 32 | 28 |
| Dyspnea | 32 | 7 |
| Viral infections | 31 | 14 |
| Thrombosis | 25 | 11 |
| Diarrhea | 24 | 7 |
| Rash | 23 | 3 |
| Headache | 21 | 4 |
| Hypertension | 20 | 13 |
| Dizziness | 16 | 0 |
Selected laboratory abnormalities during treatment with Jakafi are shown in Table 17.
| ||
| Jakafi (N=71) | ||
| Worst grade during treatment | ||
| Laboratory Parameter | All Grades *(%) | Grade 3-4(%) |
| Hematology | ||
| Anemia | 75 | 45 |
| Thrombocytopenia | 75 | 61 |
| Neutropenia | 58 | 40 |
| Chemistry | ||
| Elevated ALT | 48 | 8 |
| Elevated AST | 48 | 6 |
| Hypertriglyceridemia | 11 | 1 |
Chronic Graft-Versus-Host Disease
In a Phase 3, randomized, open-label, multi-center study, 165 patients were treated with Jakafi and 158 patients were treated with best available therapy for cGVHD failing treatment with steroids with or without other immunosuppressive drugs [ see Clinical Studies ( 14.4)] ; sixty-five patients crossed over from best available therapy to treatment with Jakafi, for a total of 230 patients treated with Jakafi. The median duration of exposure to Jakafi for the study was 49.7 weeks (range, 0.7 to 144.9 weeks) in the Jakafi arm. One hundred and nine (47%) patients were on Jakafi for at least 1 year.
There were five fatal adverse reactions to Jakafi, including 1 from toxic epidermal necrolysis and 4 from neutropenia, anemia and/or thrombocytopenia. An adverse reaction resulting in treatment discontinuation occurred in 18% of patients treated with Jakafi. An adverse reaction resulting in dose modification occurred in 27%, and an adverse reaction resulting in treatment interruption occurred in 23%. The most common hematologic adverse reactions (incidence > 35%) are anemia and thrombocytopenia. The most common nonhematologic adverse reactions (incidence ≥ 20%) are infections (pathogen not specified) and viral infection.
Table 18 presents the most frequent nonlaboratory adverse reactions occurring up to Cycle 7 Day 1 of randomized treatment.
| Adverse Reaction * | Jakafi (N = 165) | Best Available Therapy (N = 158) | ||
| All Grades † (%) | Grade ≥ 3 (%) | All Grades (%) | Grade ≥ 3 (%) | |
| Infections and infestations | ||||
| Infections (pathogen not specified) | 45 | 15 | 44 | 16 |
| Viral infections | 28 | 5 | 23 | 5 |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal pain | 18 | 1 | 13 | 0 |
| General disorders and administration site conditions | ||||
| Pyrexia | 16 | 2 | 9 | 1 |
| Fatigue | 13 | 1 | 10 | 2 |
| Edema | 10 | 1 | 12 | 1 |
| Vascular disorders | ||||
| Hypertension | 16 | 5 | 13 | 7 |
| Hemorrhage | 12 | 2 | 15 | 2 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 13 | 0 | 8 | 0 |
| Dyspnea | 11 | 1 | 8 | 1 |
| Gastrointestinal disorders | ||||
| Nausea | 12 | 0 | 13 | 2 |
| Diarrhea | 10 | 1 | 13 | 1 |
Clinically relevant laboratory abnormalities are shown in Table 19.
| Laboratory Test | Jakafi(N = 165) | Best Available Therapy(N = 158) | ||
| All Grades † (%) | Grade ≥ 3 (%) | All Grades (%) | Grade ≥ 3 (%) | |
| Hematology | ||||
| Anemia | 82 | 13 | 75 | 8 |
| Neutropenia | 27 | 12 | 23 | 9 |
| Thrombocytopenia | 58 | 20 | 54 | 17 |
| Chemistry | ||||
| Hypercholesterolemia | 88 | 10 | 85 | 8 |
| Elevated AST | 65 | 5 | 54 | 6 |
| Elevated ALT | 73 | 11 | 71 | 16 |
| Gamma glutamyltransferase increased | 81 | 42 | 75 | 38 |
| Creatinine increased | 47 | 1 | 40 | 2 |
| Elevated lipase | 38 | 12 | 30 | 9 |
| Elevated amylase | 35 | 8 | 25 | 4 |
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