Xeljanz

Xeljanz

tofacitinib

Manufacturer:

Pfizer

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Tofacitinib.
Description
Each 5 mg film-coated tablet contains 8.078 mg of tofacitinib citrate equivalent to 5 mg of tofacitinib free base active pharmaceutical ingredient. Each 5 mg tablet also contains 61.307 mg lactose monohydrate.
Excipients/Inactive Ingredients: Microcrystalline cellulose, Lactose monohydrate, Croscarmellose sodium, Magnesium stearate.
Film Coat for 5 mg tablets: Opadry II White (33G28523) containing: HPMC 2910/Hypromellose 6cP, Titanium dioxide, Lactose monohydrate, Macrogol/PEG3350, Triacetin (glycerol triacetate).
Action
Pharmacology: Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1377 nM, respectively. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.
Pharmacodynamics: Treatment with tofacitinib was associated with dose-dependent reductions of circulating CD16/56+ natural killer cells, with estimated maximum reductions occurring at approximately 8-10 weeks after initiation of therapy. These changes generally resolved within 2-6 weeks after discontinuation of treatment. Treatment with tofacitinib was associated with dose-dependent increases in B cell counts. Changes in circulating T-lymphocyte counts and T-lymphocyte subsets (CD3+, CD4+ and CD8+) were small and inconsistent. The clinical significance of these changes is unknown.
Total serum IgG, IgM, and IgA levels after 6-month dosing in patients with rheumatoid arthritis were lower than placebo; however, changes were small and not dose-dependent.
After treatment with tofacitinib in patients with rheumatoid arthritis, rapid decreases in serum C-reactive protein (CRP) were observed and maintained throughout dosing. Changes in CRP observed with tofacitinib treatment do not reverse fully within 2 weeks after discontinuation, indicating a longer duration of pharmacodynamic activity compared to the pharmacokinetic half-life.
Clinical Studies: The tofacitinib clinical development program included two dose-ranging trials and five confirmatory trials. Although other doses have been studied, the recommended dose of tofacitinib is 5 mg twice daily.
Dose-Ranging Trials: Dose selection for tofacitinib was based on two pivotal dose-ranging trials.
Dose-Ranging Study 1 was a 6-month monotherapy trial in 384 patients with active rheumatoid arthritis who had an inadequate response to a DMARD. Patients who previously received adalimumab therapy were excluded. Patients were randomized to 1 of 7 monotherapy treatments: tofacitinib 1, 3, 5, 10 or 15 mg twice daily, adalimumab 40 mg subcutaneously every other week for 10 weeks followed by tofacitinib 5 mg twice daily for 3 months, or placebo.
Dose-Ranging Study 2 was a 6-month trial in which 507 patients with active rheumatoid arthritis who had an inadequate response to MTX alone received one of 6 dose regimens of tofacitinib (20 mg once daily; 1, 3, 5, 10 or 15 mg twice daily), or placebo added to background MTX.
The results of tofacitinib-treated patients achieving ACR20 responses in Studies 1 and 2 are shown in Figure 1. Although a dose-response relationship was observed in Study 1, the proportion of patients with an ACR20 response did not clearly differ between the 10 mg and 15 mg doses. In Study 2, a smaller portion of patients achieved an ACR20 response in the placebo and tofacitinib 1 mg groups compared to patients treated with the other tofacitinib doses. However, there was no difference in the proportion of responders among patients treated with tofacitinib 3, 5, 10, 15 mg twice daily or 20 mg once daily doses. (See Figure 1.)

Click on icon to see table/diagram/image

Study 1 was a dose-ranging monotherapy trial not designed to provide comparative effectiveness data and should not be interpreted as evidence of superiority to adalimumab.
Confirmatory Trials: Study RA-I (NCT00814307) was a 6-month monotherapy trial in which 610 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a DMARD (nonbiologic or biologic) received tofacitinib 5 or 10 mg twice daily or placebo. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of tofacitinib 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, changes in Health Assessment Questionnaire - Disability Index (HAQ-DI), and rates of Disease Activity Score DAS28-4(ESR) less than 2.6.
Study RA-II (NCT00856544) was a 12-month trial in which 792 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a nonbiologic DMARD received tofacitinib 5 or 10 mg twice daily or placebo added to background DMARD treatment (excluding potent immunosuppresive treatments such as azathioprine or cyclosporine). At the Month 3 visit, nonresponding patients were advanced in a blinded fashion to a second predetermined treatment of tofacitinib 5 or 10 mg twice daily. At the end of Month 6, all placebo patients were advanced to their second predetermined treatment in a blinded fashion. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, changes in HAQ-DI at Month 3, and rates of DAS28-4(ESR) less than 2.6 at Month 6.
Study RA-III (NCT00853385) was a 12-month trial in 717 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX. Patients received tofacitinib 5 or 10 mg twice daily, adalimumab 40 mg subcutaneously every other week, or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved in ACR20 response at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.
Study RA-IV (NCT00847613) was a 2-year trial with a planned analysis at 1 year in which 797 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX received tofacitinib 5 or 10 mg twice daily or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, mean change from baseline in van der Heijde-modified total Sharp Score (mTSS) at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.
Study RA-V (NCT00960440) was a 6-month trial in which 399 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to at least one approved TNF-blocking biologic agent received tofacitinib 5 or 10 mg twice daily or placebo added to background MTX. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of tofacitinib 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, HAQ-DI, and DAS28-4(ESR) less than 2.6.
Clinical Response: The percentages of tofacitinib-treated patients achieving ACR20, ACR50, and ACR70 responses in Studies RA-I, IV, and V are shown in Table 1. Similar results were observed with Studies RA-II and III. In trials RA-I through V, patients treated with either 5 or 10 mg twice daily tofacitinib had higher ACR20, ACR50, and ACR70 response rates versus placebo, with or without background DMARD treatment, at Month 3 and Month 6. Higher ACR20 response rates were observed within 2 weeks compared to placebo. In the 12-month trials, ACR response rates in tofacitinib-treated patients were consistent at 6 and 12 months. (See Table 1.)

Click on icon to see table/diagram/image

In Study RA-IV, a greater proportion of patients treated with tofacitinib 5 mg or 10 mg twice daily plus MTX achieved a low level of disease activity as measured by a DAS28-4(ESR) less than 2.6 at 6 months compared to those treated with MTX alone (Table 2). (See Table 2.)

Click on icon to see table/diagram/image

The results of the components of the ACR response criteria for Study RA-IV are shown in Table 3. Similar results were observed for tofacitinib in Studies RA-I, II, III and V. (See Table 3.)

Click on icon to see table/diagram/image

The percent of ACR20 responders by visit for Study RA-IV is shown in Figure 2. Similar responses were observed for tofacitinib in Studies RA-I, II, III and V. (See Figure 2.)

Click on icon to see table/diagram/image

Radiographic Response: One study was conducted to evaluate the effect of tofacitinib on structural joint damage. In Study RA-IV, progression of structural joint damage was assessed radiographically and expressed as change from baseline in mTSS and its components, the erosion score and joint space narrowing score, at Months 6 and 12. The proportion of patients with no radiographic progression (mTSS change less than or equal to 0) was also assessed.
In Study RA-IV, tofacitinib 10 mg twice daily plus background MTX reduced the progression of structural damage compared to placebo plus MTX at Month 6. When given at a dose of 5 mg twice daily, tofacitinib exhibited similar effects on mean progression of structural damage (not statistically significant). These results are shown in Table 4. Analyses of erosion and joint space narrowing scores were consistent with the overall results.
In the placebo plus MTX group, 74% of patients experienced no radiographic progression at Month 6 compared to 84% and 79% of patients treated with tofacitinib plus MTX 5 or 10 mg twice daily. (See Table 4.)

Click on icon to see table/diagram/image

Physical Function Response: Improvement in physical functioning was measured by the HAQ-DI. Patients receiving tofacitinib 5 and 10 mg twice daily demonstrated greater improvement from baseline in physical functioning compared to placebo at Month 3.
The mean (95% CI) difference from placebo in HAQ-DI improvement from baseline at Month 3 in Study RA-III was -0.22 (-0.35, -0.10) in patients receiving 5 mg tofacitinib twice daily and -0.32 (-0.44, -0.19) in patients receiving 10 mg tofacitinib twice daily. Similar results were obtained in Studies RA-I, II, IV and V. In the 12-month trials, HAQ-DI results in tofacitinib-treated patients were consistent at 6 and 12 months.
Other Health-Related Outcomes: General health status was assessed by the Short Form health survey (SF-36). In Studies RA-I, IV, and V, patients receiving tofacitinib 5 mg twice daily or tofacitinib 10 mg twice daily demonstrated greater improvement from baseline compared to placebo in physical component summary (PCS), mental component summary (MCS) scores and in all 8 domains of the SF-36 at Month 3.
Pharmacokinetics: Following oral administration of tofacitinib, peak plasma concentrations are reached within 0.5-1 hour, elimination half-life is about 3 hours and a dose-proportional increase in systemic exposure was observed in the therapeutic dose range. Steady state concentrations are achieved in 24-48 hours with negligible accumulation after twice daily administration.
Absorption: The absolute oral bioavailability of tofacitinib is 74%. Co-administration of tofacitinib with a high-fat meal resulted in no changes in AUC while Cmax was reduced by 32%. In clinical trials, tofacitinib was administered without regard to meals (see Dosage & Administration).
Distribution: After intravenous administration, the volume of distribution is 87 L. The protein binding of tofacitinib is approximately 40%. Tofacitinib binds predominantly to albumin and does not appear to bind to α1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma.
Metabolism and Excretion: Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity. The pharmacologic activity of tofacitinib is attributed to the parent molecule.
Population Pharmacokinetics in Rheumatoid Arthritis Patients: Population pharmacokinetic analyses indicated that the coefficient of variation (%) in AUC of tofacitinib for patients with rheumatoid arthritis was 22.0% (Table 5). (See Table 5.)

Click on icon to see table/diagram/image

Specific Populations: Covariate evaluation as part of population PK analyses in patient populations indicated no clinically relevant change in tofacitinib exposure, after accounting for differences in renal function (i.e., creatinine clearance) between patients, based on age, weight, gender and race (Figure 3). An approximately linear relationship between body weight and volume of distribution was observed, resulting in higher peak (Cmax) and lower trough (Cmin) concentrations in lighter patients. However, this difference is not considered to be clinically relevant.
The effect of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of tofacitinib is shown in Figure 3. (See Figure 3.)

Click on icon to see table/diagram/image

In subjects with ESRD maintained on hemodialysis, mean AUC was approximately 40% higher compared with historical healthy subject data, consistent with approximately 30% contribution of renal clearance to the total clearance of tofacitinib. Dose adjustment is recommended in ESRD patients maintained on hemodialysis (see Dosage & Administration) for dosage adjustment in RA patients.
Drug Interaction Studies: Potential for Tofacitinib to Influence the Pharmacokinetics of Other Drugs: In vitro studies indicate that tofacitinib does not significantly inhibit or induce the activity of the major human drug-metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations exceeding 160 times the steady state Cmax of a 5 mg twice daily dose. These in vitro results were confirmed by a human drug interaction study showing no changes in the pharmacokinetics of midazolam, a highly sensitive CYP3A4 substrate, when co-administered with tofacitinib.
In rheumatoid arthritis patients, the oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in rheumatoid arthritis patients. Therefore, co-administration with tofacitinib is not expected to result in clinically relevant increases in the metabolism of CYP substrates in rheumatoid arthritis patients.
In vitro data indicate that the potential for tofacitinib to inhibit transporters such as P-glycoprotein, organic anionic or cationic transporters at therapeutic concentrations is low.
Dosing recommendations for co-administered drugs following administration with tofacitinib are shown in Figure 4. (See Figure 4.)

Click on icon to see table/diagram/image

Potential for Other Drugs to Influence the Pharmacokinetics of Tofacitinib: Since tofacitinib is metabolized by CYP3A4, interaction with drugs that inhibit or induce CYP3A4 is likely. Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to substantially alter the Pharmacokinetics of tofacitinib (see Figure 5).

Click on icon to see table/diagram/image

Toxicology: Non-Clinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 39-week toxicology study in monkeys, tofacitinib at exposure levels approximately 6 times the recommended dose of 5 mg twice daily (on an AUC basis at oral doses of 5 mg/kg twice daily) produced lymphomas. No lymphomas were observed in this study at exposure levels 1 times the recommended dose of 5 mg twice daily (on an AUC basis at oral doses of 1 mg/kg twice daily).
The carcinogenic potential of tofacitinib was assessed in 6-month rasH2 transgenic mouse carcinogenicity and 2-year rat carcinogenicity studies. Tofacitinib, at exposure levels approximately 34 times the recommended dose of 5 mg twice daily (on an AUC basis at oral doses of 200 mg/kg/day) was not carcinogenic in mice.
In the 24-month oral carcinogenicity study in Sprague-Dawley rats, tofacitinib caused benign Leydig cell tumors, hibernomas (malignancy of brown adipose tissue), and benign thymomas at doses greater than or equal to 30 mg/kg/day (approximately 42 times the exposure levels at the recommended dose of 5 mg twice daily on an AUC basis).The relevance of benign Leydig cell tumors to human risk is not known.
Tofacitinib was not mutagenic in the bacterial reverse mutation assay. It was positive for clastogenicity in the in vitro chromosome aberration assay with human lymphocytes in the presence of metabolic enzymes, but negative in the absence of metabolic enzymes. Tofacitinib was negative in the in vivo rat micronucleus assay and in the in vitro CHO-HGPRT assay and the in vivo rat hepatocyte unscheduled DNA synthesis assay.
In rats, tofacitinib at exposure levels approximately 17 times the recommended dose of 5 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day) reduced female fertility due to increased post-implantation loss. There was no impairment of female rat fertility at exposure levels of tofacitinib equal to the recommended dose of 5 mg twice daily (on an AUC basis at oral doses of 1 mg/kg/day). Tofacitinib exposure levels at approximately 133 times the recommended dose of 5 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/day) had no effect on male fertility, sperm motility, or sperm concentration.
Indications/Uses
Rheumatoid Arthritis: XELJANZ is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs).
Limitations of Use: Use of XELJANZ in combination with biologic DMARDs or with potent immunosuppressants, such as azathioprine and cyclosporine is not recommended.
Dosage/Direction for Use
Important Administration Instructions: Do not initiate XELJANZ in patients with an absolute lymphocyte count less than 500 cells/mm3, an absolute neutrophil count (ANC) <1000 cells/mm3 or who have hemoglobin levels less than9 g/dL.
Dose interruption is recommended for management of lymphopenia, neutropenia and anemia (see Precautions and Adverse Reactions).
Interrupt use of XELJANZ if a patient develops a serious infection until the infection is controlled.
Take XELJANZ with or without food (see Pharmacology: Pharmacokinetics under Actions).
Recommended Dosage: Table 6 displays the recommended adult daily dosage of XELJANZ and dosage adjustments for patients receiving CYP2C19 and/or CYP3A4 inhibitors, in patients with moderate or severe renal impairment (including but not limited to those with severe insufficiency who are undergoing hemodialysis) or moderate hepatic impairment, with lymphopenia, neutropenia, or anemia. (See Table 6.)

Click on icon to see table/diagram/image

Hepatic Impairment: Severe Impairment: XELJANZ has not been studied in patients with severe hepatic impairment; therefore, use of XELJANZ in patients with severe hepatic impairment is not recommended.
Moderate Impairment: XELJANZ-treated patients with moderate hepatic impairment had greater tofacitinib blood concentration than XELJANZ-treated patients with normal hepatic function (see Pharmacology: Pharmacokinetics under Actions). Higher blood concentrations may increase the risk of some adverse reactions. Therefore, dosage adjustment of XELJANZ is recommended in patients with moderate hepatic impairment (see previously mentioned).
Mild Impairment: No dosage adjustment of XELJANZ is required in patients with mild hepatic impairment.
Hepatitis B or C Serology: The safety and efficacy of XELJANZ have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology.
Renal Impairment: Moderate and Severe Impairment: XELJANZ-treated patients with moderate or severe renal impairment had greater tofacitinib blood concentrations than XELJANZ-treated patients with normal renal function. Therefore, dosage adjustment of XELJANZ is recommended in patients with moderate or severe renal impairment (including but not limited to those with severe insufficiency who are undergoing hemodialysis).
Mild impairment: No dosage adjustment is required in patients with mild renal impairment.
Geriatric Use: Of the 3315 patients who enrolled in rheumatoid arthritis Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among tofacitinib-treated subjects 65 years of age and older was higher than among those under the age of 65.
As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly (see Precautions).
Pediatric Use: The safety and effectiveness of XELJANZ in pediatric patients have not been established.
Use in Diabetics: As there is a higher incidence of infection in diabetic population in general, caution should be used when treating patients with diabetes.
Overdosage
There is no specific antidote for overdose with tofacitinib. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions.
In a study in subjects with end stage renal disease (ESRD) undergoing hemodialysis, plasma tofacitinib concentrations declined more rapidly during the period of hemodialysis and dialyzer efficiency, calculated as dialyzer clearance/blood flow entering the dialyzer, was high [mean (SD) = 0.73 (0.15)]. However, due to the significant non-renal clearance of tofacitinib, the fraction of total elimination occurring by hemodialysis was small, and thus limits the value of hemodialysis for treatment of overdose with XELJANZ.
Contraindications
Hypersensitivity to the active substance or to any of the excipients (see Description).
Special Precautions
Serious Infections: Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving immunomodulatory agents, including biologic DMARDs and XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcus, histoplasmosis, esophageal candidiasis, multidermatomal herpes zoster, cytomegalovirus infection, BK virus infections, and listeriosis were reported with XELJANZ. Some patients have presented with disseminated rather than localized disease, and rheumatoid arthritis patients were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids which, in addition to rheumatoid arthritis may predispose them to infections. Other serious infections that were not reported in clinical studies, may also occur (e.g., coccidioidomycosis).
XELJANZ should not be initiated in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ in patients with chronic or recurrent infections, or those who have been exposed to tuberculosis, or with a history of a serious or an opportunistic infection, or have resided or travelled in areas of endemic tuberculosis or endemic mycoses; or have underlying conditions that may predispose them to infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ. XELJANZ should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with XELJANZ should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient, appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.
As there is a higher incidence of infections in the elderly and in the diabetic populations in general, caution should be used when treating the elderly and patients with diabetes (see Dosage & Administration). Caution is also recommended in patients with a history of chronic lung disease as they may be more prone to infections. Events of interstitial lung disease (some of which had a fatal outcome) have been reported in patients treated with XELJANZ, a Janus-kinase (JAK) inhibitor, in clinical trials and in the post-marketing setting although the role of JAK inhibition in these events is not known.
Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Discontinuation and monitoring criteria for lymphopenia are discussed in Dosage & Administration.
Tuberculosis: Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during administration of XELJANZ.
Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering XELJANZ.
Antituberculosis therapy should also be considered prior to administration of XELJANZ in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a health care professional with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating antituberculosis therapy is appropriate for an individual patient.
Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.
Viral Reactivation: Viral reactivation has been reported with DMARD treatment and cases of herpes virus reactivation (e.g., herpes zoster) were observed in clinical studies with XELJANZ. Post-marketing cases of hepatitis B reactivation have been reported in patients treated with XELJANZ. The impact of XELJANZ on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with XELJANZ. The risk of herpes zoster appears to be higher in Japanese and Korean patients treated with XELJANZ.
Malignancy and Lymphoproliferative Disorder (Excluding Non-melanoma Skin Cancer [NMSC]): Consider the risks and benefits of XELJANZ treatment prior to initiating therapy in patients with current or a history of malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ in patients who develop a malignancy. The possibility exists for XELJANZ to affect host defenses against malignancies.
Lymphomas have been observed in patients treated with XELJANZ. Patients with rheumatoid arthritis, particularly those with highly active disease may be at a higher risk (up to several-fold) than the general population for the development of lymphoma. The role of XELJANZ, in the development of lymphoma is uncertain.
Other malignancies were observed in clinical studies and the post-marketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer and pancreatic cancer.
The role of treatment with XELJANZ on the development and course of malignancies is not known.
In controlled Phase 3 clinical studies in rheumatoid arthritis patients, 26 malignancies (excluding NMSC) including 5 lymphoma were diagnosed in 26 patients receiving XELJANZ/XELJANZ plus DMARD, compared to 0 malignancies (excluding NMSC) in patients in the placebo/placebo plus DMARD and 2 in 2 patients in the adalimumab group, 1 in 1 patient in the methotrexate group. 3800 patients (3942 patient-years of observation) were treated with XELJANZ for durations up to 2 years while 681 patients (203 patient-years of observation) were treated with placebo for a maximum of 6 months and 204 patients (179 patient-years of observation) were treated with adalimumab for 12 months. The exposure-adjusted incidence rate for malignancies and lymphoma was 0.66 and 0.13 events per 100 patient-years, respectively, in the XELJANZ groups. In the long-term safety population (4867 patients), in rheumatoid arthritis studies, the rate of malignancies (excluding NMSC) and lymphoma was 0.97 and 0.09 events per 100 patient-years respectively, consistent with the rate observed in the controlled period.
Non-melanoma Skin Cancer: Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
Gastrointestinal Perforations: Events of gastrointestinal perforation have been reported in clinical trials, although the role of JAK inhibition in these events is not known. Events were primarily reported as diverticular perforation, peritonitis, abdominal abscess and appendicitis. In the rheumatoid arthritis clinical trials, the incidence rate of gastrointestinal perforation across all studies (Phase 1, Phase 2, Phase 3 and long term extension) for all treatments groups all doses was 0.11 events per 100 patient-years with XELJANZ therapy. Rheumatoid arthritis patients who developed gastrointestinal perforations were taking concomitant non-steroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids. The relative contribution of these concomitant medications vs. XELJANZ to the development of gastrointestinal perforations is not known.
XELJANZ should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation.
Hypersensitivity: Reactions such as angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving XELJANZ. Some events were serious. Many of these events occurred in patients that have a history of multiple allergies. If a serious hypersensitivity reaction occurs, promptly discontinue XELJANZ while evaluating the potential cause or causes of the reaction.
Laboratory Parameters: Lymphocytes: Lymphocyte counts <500 cells/mm3 were associated with an increased incidence of treated and serious infections. It is not recommended to initiate XELJANZ treatment in patients with a low lymphocyte count (i.e., <500 cells/mm3). In patients who develop a confirmed absolute lymphocyte count <500 cells/mm3 treatment with XELJANZ is not recommended. Lymphocytes should be monitored at baseline and every 3 months thereafter. For recommended modifications based on lymphocyte counts see Dosage & Administration.
Neutrophils: Treatment with XELJANZ was associated with an increased incidence of neutropenia (<2000 cells/mm3) compared to placebo. It is not recommended to initiate XELJANZ treatment in patients with a low neutrophil count (i.e., ANC <1000 cells/mm3). For patients who develop a persistent ANC of 500-1000 cells/mm3, reduce XELJANZ dose or interrupt XELJANZ dosing until ANC is >1000 cells/mm3. In patients who develop a confirmed absolute neutrophil count <500 cells/mm3, treatment with XELJANZ is not recommended. Neutrophils should be monitored at baseline and after 4 - 8 weeks of treatment and every 3 months thereafter (see Dosage & Administration and Adverse Reactions).
Hemoglobin: It is not recommended to initiate XELJANZ treatment in patients with low hemoglobin values (i.e., <9 g/dL). Treatment with XELJANZ should be interrupted in patients who develop hemoglobin levels <8 g/dL or whose hemoglobin level drops >2 g/dL on treatment. Hemoglobin should be monitored at baseline and after 4 - 8 weeks of treatment and every 3 months thereafter (see Dosage & Administration and Adverse Reactions).
Lipids: Treatment with XELJANZ was associated with increases in lipid parameters such as total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. Assessment of lipid parameters should be performed approximately 4 - 8 weeks following initiation of XELJANZ therapy. Patients should be managed according to current local clinical guidelines for the management of hyperlipidemia. Increases in total and LDL cholesterol associated with XELJANZ may be decreased to pre-treatment levels with statin therapy.
Vaccinations: No data are available on the secondary transmission of infection by live vaccines to patients receiving XELJANZ. It is recommended that live vaccines not be given concurrently with XELJANZ. It is recommended that all patients be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy. The interval between live vaccinations and initiation of XELJANZ therapy should be in accordance with current vaccination guidelines regarding immunomodulatory agents. Consistent with these guidelines, if live zoster vaccine is administered, it should only be administered to patients with a known history of chickenpox or those that are seropositive for varicella zoster virus. Vaccination should occur at least 2 weeks but preferably 4 weeks before initiating immunomodulatory agents such as XELJANZ.
A controlled study in patients with rheumatoid arthritis on background methotrexate evaluated the humoral and cell-mediated responses to immunization with a live attenuated virus vaccine (Zostavax) indicated for prevention of herpes zoster. The immunization occurred 2 to 3 weeks before initiating a 12-week treatment with XELJANZ 5 mg twice daily or placebo. Six weeks after immunization with the zoster vaccine, XELJANZ and placebo recipients exhibited similar humoral and cell-mediated responses (mean fold change of VZV IgG antibodies 2.11 in XELJANZ 5 mg twice daily and 1.74 in placebo twice daily; VZV IgG fold-rise ≥1.5 in 57% of XELJANZ recipients and in 43% of placebo recipients; mean fold change of VZV T-cell ELISPOT Spot Forming Cells 1.5 in XELJANZ 5 mg twice daily and 1.29 in placebo twice daily). These responses were similar to those observed in healthy volunteers aged 50 years and older.
In this study one patient experienced dissemination of the vaccine strain of varicella zoster virus, 16 days after vaccination. The patient was varicella virus naive, as evidenced by no previous history of varicella infection and no anti-varicella antibodies at baseline. XELJANZ was discontinued and the subject recovered after treatment with standard doses of antiviral medication. Subsequent testing showed that this patient made robust anti-varicella T-cell and antibody responses to the vaccine approximately 6 weeks post-vaccination, but not at 2 weeks post-vaccination, as expected for a primary infection.
Effects on ability to drive and use machines: No formal studies have been conducted on the effects on the ability to drive and use machines.
Use In Pregnancy & Lactation
Pregnancy: Risk Summary: Available data with XELJANZ use in pregnant women are insufficient to establish a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with rheumatoid arthritis in pregnancy. In animal reproduction studies, fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 73 times. Further, in a peri and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73 times the recommended dose of 5 mg twice daily (see Data as follows).
Women of reproductive potential should be advised to use effective contraception during treatment with tofacitinib and for at least 4 weeks after the last dose.
The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risks in the U.S. general population of major birth defects and miscarriages are 2 to 4% and 15 to 20% of clinically recognized pregnancies, respectively.
Clinical Considerations: Disease-Associated Maternal and/or Embryo/Fetal Risk: Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.
Data: Animal Data: In a rat embryofetal developmental study, in which pregnant rats received tofacitinib during organogenesis, tofacitinib was teratogenic at exposure levels approximately 146 times the recommended dose of 5 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/day in rats). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively, and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the recommended dose of 5 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in pregnant rats).
In a rabbit embryofetal developmental study, in which pregnant rabbits received tofacitinib during the period of organogenesis, tofacitinib was teratogenic at exposure levels approximately 13 times the recommended dose of 5 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in rabbits) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the recommended dose of 5 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in pregnant rabbits).
In a peri- and postnatal development study in pregnant rats that received tofacitinib from gestation day 6 through day 20 of lactation, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the recommended dose of 5 mg twice daily (on an AUC basis at oral doses of 50 mg/kg/day in rats). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the recommended dose of 5 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in rats).
Lactation: Risk Summary: There are no data on the presence of tofacitinib in human milk, the effects on a breastfed infant, or the effects on milk production. Tofacitinib is present in the milk of lactating rats (see Data as follows). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Given the serious adverse reactions seen in adults treated with XELJANZ, such as increased risk of serious infections, advise patients that breastfeeding is not recommended during treatment and for at least 18 hours after the last dose of XELJANZ.
Data: Following administration of tofacitinib to lactating rats, concentrations of tofacitinib in milk over time paralleled those in serum, and were approximately 2 times higher in milk relative to maternal serum at all time points measured.
Females and Males of Reproductive Potential: Contraception: Females: In an animal reproduction study, tofacitinib at AUC multiples of 13 times the recommended dose of 5 mg twice daily demonstrated adverse embryo-fetal findings.
However, there is uncertainty as to how these animal findings relate to females of reproductive potential treated with the recommended clinical dose. Consider pregnancy planning and prevention for females of reproductive potential.
Infertility: Females: Based on findings in rats, treatment with XELJANZ may result in reduced fertility in females of reproductive potential. It is not known if this effect is reversible (see Pharmacology: Toxicology: Non-Clinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility under Actions).
Adverse Reactions
The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Infections (see Precautions), Malignancy and Lymphoproliferative Disorders (see Precautions), Gastrointestinal Perforations (see Precautions), Laboratory Abnormalities (see Precautions).
Clinical Trials Experience: Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.
Rheumatoid Arthritis: The clinical studies described in the following sections were conducted using XELJANZ. Although other doses of XELJANZ have been studied, the recommended dose of XELJANZ is 5 mg twice daily.
The following data includes two Phase 2 and five Phase 3 double-blind, controlled, multicenter trials. In these trials, patients were randomized to doses of XELJANZ 5 mg twice daily (292 patients) and 10 mg twice daily (306 patients) monotherapy, XELJANZ 5 mg twice daily (1044 patients) and 10 mg twice daily (1043 patients) in combination with DMARDs (including methotrexate) and placebo (809 patients). All seven protocols included provisions for patients taking placebo to receive treatment with XELJANZ at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore, some analyses that follow include patients who changed treatment by design or by patient response from placebo to XELJANZ in both the placebo and XELJANZ group of a given interval. Comparisons between placebo and XELJANZ were based on the first 3 months of exposure, and comparisons between XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily were based on the first 12 months of exposure.
The long-term safety population includes all patients who participated in a double-blind, controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies. The design of the long-term safety studies allowed for modification of XELJANZ doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose.
The most common serious adverse reactions were serious infections (see Precautions).
The proportion of patients who discontinued treatment due to any adverse reaction during the 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for patients taking XELJANZ and 3% for placebo-treated patients.
Overall Infections: In the seven controlled trials, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the 5 mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group.
The most commonly reported infections with XELJANZ were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).
Serious Infections: In the seven controlled trials, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined 5 mg twice daily and 10 mg twice daily XELJANZ group minus placebo.
In the seven controlled trials, during the 0 to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 33 patients (2.7 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ.
The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection (see Precautions).
Tuberculosis: In the seven controlled trials, during the 0 to 3 months exposure, tuberculosis was not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ.
In the seven controlled trials, during the 0 to 12 months exposure, tuberculosis was reported in 0 patients who received 5 mg twice daily of XELJANZ and 6 patients (0.5 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ.
Cases of disseminated tuberculosis were also reported. The median XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days) (see Precautions).
Opportunistic Infections (excluding tuberculosis): In the seven controlled trials, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ.
In the seven controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 4 patients (0.3 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ.
The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days) (see Precautions).
Malignancy: In the seven controlled trials, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient-years) who received either XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 0.3 (-0.1, 0.7) events per 100 patient-years for the combined 5 mg and 10 mg twice daily XELJANZ group minus placebo.
In the seven controlled trials, during the 0 to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 7 patients (0.6 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. One of these malignancies was a case of lymphoma that occurred during the 0 to 12 month period in a patient treated with XELJANZ 10 mg twice daily.
The most common types of malignancy, including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma (see Precautions).
Laboratory Abnormalities: Lymphopenia: In the controlled clinical trials, confirmed decreases in absolute lymphocyte counts below 500 cells/mm3 occurred in 0.04% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure.
Confirmed lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections (see Precautions).
Neutropenia: In the controlled clinical trials, confirmed decreases in ANC below 1000 cells/mm3 occurred in 0.07% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure.
There were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group.
There was no clear relationship between neutropenia and the occurrence of serious infections.
In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the controlled clinical trials (see Precautions).
Liver Enzyme Elevations: Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3x ULN) were observed in patients treated with XELJANZ. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in XELJANZ dose, resulted in decrease or normalization of liver enzymes.
In the controlled monotherapy trials (0-3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and XELJANZ 5 mg, and 10 mg twice daily groups. In the controlled background DMARD trials (0-3 months), ALT elevations greater than 3x ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3x ULN were observed in 0.6%, 0.5% and 0.4% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively.
One case of drug-induced liver injury was reported in a patient treated with XELJANZ 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3x ULN and bilirubin elevations greater than 2x ULN, which required hospitalizations and a liver biopsy.
Lipid Elevations: In the controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first 3 months of exposure in the controlled clinical trials are summarized as fiollows: Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.
Mean HDL cholesterol increased by 10% in the XELJANZ 5 mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.
Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients.
In a controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.
In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the controlled clinical trials.
Serum Creatinine Elevations: In the controlled clinical trials, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from XELJANZ treatment due to the protocol-specified discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical significance of the observed serum creatinine elevations is unknown.
Other Adverse Reactions: Adverse reactions occurring in 2% or more of patients on 5 mg twice daily or 10 mg twice daily XELJANZ and at least 1% greater than that observed in patients on placebo with or without DMARD are summarized in Table 7. (See Table 7.)

Click on icon to see table/diagram/image

Other adverse reactions occurring in controlled and open-label extension studies included: Blood and lymphatic system disorders: Anemia.
Infections and infestations: Diverticulitis.
Metabolism and nutrition disorders: Dehydration.
Psychiatric disorders: Insomnia.
Nervous system disorders: Paresthesia.
Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion, interstitial lung disease (cases were limited to patients with rheumatoid arthritis and some were fatal).
Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nausea.
Hepatobiliary disorders: Hepatic steatosis.
Skin and subcutaneous tissue disorders: Rash, erythema, pruritus.
Musculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swelling.
Neoplasms benign, malignant and unspecified (including cysts and polyps): Non-melanoma skin cancers.
General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema.
Post-marketing Experience: Immune system disorders: Drug hypersensitivity (events such as angioedema and urticaria have been observed).
Drug Interactions
Table 8 includes drugs with clinically important drug interactions when administered concomitantly with XELJANZ and instructions for preventing or managing them. (See Table 8.)

Click on icon to see table/diagram/image
Caution For Usage
Special precautions for disposal and other handling: No special requirements.
Incompatibilities: Not applicable.
Storage
Store below 30°C.
ATC Classification
L04AA29 - tofacitinib ; Belongs to the class of selective immunosuppressive agents. Used to induce immunosuppression.
Presentation/Packing
FC tab 5 mg (white, round immediate-release, debossed with 'Pfizer' on one side and 'JKI 5' on the other) x 56's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in