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Each film-coated tablet contains:
Tofacitinib citrate equivalent to Tofacitinib ……. 5 mg
Excipients .......................................................... q.s.
Color: Titanium Dioxide IP
5 mg film coated tablets for oral use
Tofacitinib film-coated tablets are 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 nonbiologic disease-modifying antirheumatic drugs (DMARDs).
Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of conditions for which tofacitinib is indicated.
The recommended dose is 5 mg administered twice daily.
Patients treated with tofacitinib 5 mg film-coated tablets twice daily.
Tofacitinib total daily dose should be reduced by half in patients receiving potent inhibitors of cytochrome P450 (CYP)3A4 (e.g., ketoconazole) and in patients receiving 1 or more concomitant medicinal products that result in both moderate inhibitions of CYP3A4 as well as potent inhibition of CYP2C19 (e.g., fluconazole) as follows:
No dose adjustment is required in patients aged 65 years and older. There is limited data in patients aged 75 years and older.
| Hepatic Impairment Category | Classification | Dose adjustment in hepatic impairment for different strength tablets |
|---|---|---|
| Mild | Child Pugh A | No dose adjustment required |
| Moderate | Child Pugh B |
Dose should be reduced to 5 mg once daily when the indicated dose in the presence of normal hepatic function is 5 mg twice daily. Dose should be reduced to 5 mg twice daily when the indicated dose in the presence of normal hepatic function is 10 mg twice daily |
| Severe | Child Pugh C | Tofacitinib should not be used in patients with severe hepatic impairment |
| Renal Impairment Category | Classification | Dose adjustment in renal impairment for different strength tablets |
|---|---|---|
| Mild | 50-80 mL/min | No dose adjustment required |
| Moderate | 30-49 mL/min | No dose adjustment required |
| Severe (including patients undergoing haemodialysis) |
< 30 mL/min |
Dose should be reduced to 5 mg once daily when the indicated dose in the presence of normal renal function is 5 mg twice daily. Dose should be reduced to 5 mg twice daily when the indicated dose in the presence of normal renal function is 10 mg twice daily. Patients with severe renal impairment should remain on a reduced dose even after haemodialysis |
Dose adjustment for renal impairment
The safety and efficacy of tofacitinib in children aged 0 to less than 18 years have not been established.
Oral use.
Tofacitinib is given orally with or without food.
For patients who have difficulties swallowing, tofacitinib tablets may be crushed and taken with water.
Tofacitinib is contraindicated in:
Tofacitinib has not been studied and its use should be avoided in combination with biologics such as TNF antagonists, interleukin (IL)-1R antagonists, IL-6R antagonists, anti-CD20 monoclonal antibodies, IL-17 antagonists, IL-12/IL-23 antagonists, anti-integrins, selective co-stimulation modulators and potent immunosuppressants such as azathioprine, 6-mercaptopurine, ciclosporine and tacrolimus because of the possibility of increased immunosuppression and increased risk of infection.
There was a higher incidence of adverse events for the combination of tofacitinib with methotrexate versus tofacitinib as monotherapy in RA clinical studies.
The use of tofacitinib in combination with phosphodiesterase 4 inhibitors has not been studied in tofacitinib clinical studies.
Serious VTE events including pulmonary embolism (PE), some of which were fatal, and deep vein thrombosis (DVT), have been observed in patients taking tofacitinib. A dose dependent increased risk for VTE was observed in a clinical study with tofacitinib compared to TNF inhibitors.
Tofacitnib should be used with caution in patients with known risk factors for VTE, regardless of indication and dosage.
VTE risk factors include previous VTE, patients undergoing major surgery, immobilisation, myocardial infarction (within previous 3 months), heart failure, use of combined hormonal contraceptives or hormone replacement therapy, inherited coagulation disorder, malignancy. Additional VTE risk factors such as age, obesity (BMI ≥30), diabetes, hypertension and smoking status should also be considered. Patients should be re-evaluated periodically during tofacitinib treatment to assess for changes in VTE risk.
Promptly evaluate patients with signs and symptoms of VTE and discontinue tofacitinib in patients with suspected VTE, regardless of dose or indication.
Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib. The risk of opportunistic infections is higher in Asian geographic regions. Rheumatoid arthritis patients taking corticosteroids may be predisposed to infection.
Tofacitinib should not be initiated in patients with active infections, including localised infections. The risks and benefits of treatment should be considered prior to initiating tofacitinib in patients:
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with tofacitinib. Treatment 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 tofacitinib 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. In patients over 65 years of age tofacitinib should only be considered if no suitable alternative treatment is available.
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.
Tuberculosis
The risks and benefits of treatment should be considered prior to initiating tofacitinib in patients:
Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during administration of tofacitinib.
Patients with latent TB, who test positive, should be treated with standard antimycobacterial therapy before administering tofacitinib.
Antituberculos is therapy should also be considered prior to administration of tofacitinib in patients who test negative forTB but who have a past history of latent or active TB and where an adequate course of treatment cannot be confirmed; or those who test negative but who have risk factors for TB infection. Consultation with a healthcare professional with expertise in the treatment of TB 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 TB, including patients who tested negative for latent TB infection prior to initiating therapy.
Viral reactivation and cases of herpes virus reactivation (e.g., herpes zoster) were observed in clinical studies with tofacitinib. In patients treated with tofacitinib, the incidence of herpes zoster appears to be increased in:
The impact of tofacitinib on chronic viral hepatitis reactivation is unknown. Patients 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 tofacitinib.
The risks and benefits of tofacitinib treatment should be considered prior to initiating therapy in patients with current or history of malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing tofacitinib in patients who develop a malignancy. The possibility exists for tofacitinib to affect host defences against malignancies.
Lymphomas have been observed in patients treated with tofacitinib. Patients with RA, 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 effect of tofacitinib on 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 effect of tofacitinib on the development and course of malignancies is not known.
NMSCs have been reported in patients treated with tofacitinib. The risk of NMSC may be higher in patients treated with tofacitinib 10 mg twice daily than in patients treated with 5 mg twice daily. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
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 tofacitinib in RA clinical trials and in the post-marketing setting although the role of Janus kinase (JAK) inhibition in these events is not known. Asian RA patients are known to be at higher risk of interstitial lung disease, thus caution should be exercised in treating these patients.
Events of gastrointestinal perforation have been reported in clinical trials although the role of JAK inhibition in these events is not known. Tofacitinib 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 with concomitant use of corticosteroids and/or nonsteroidal anti-inflammatory drugs). Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of gastrointestinal perforation.
RA patients have an increased risk for cardiovascular disorders. Patients treated with tofacitinib should have risk factors (e.g., hypertension, hyperlipidaemia) managed as part of usual standard of care.
Treatment with tofacitinib was associated with an increased incidence of liver enzyme elevation in some patients. Caution should be exercised when considering initiation of tofacitinib treatment in patients with elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST), particularly when initiated incombination with potentially hepatotoxic medicinal products such as methotrexate. Following initiation, routine monitoring of livertests and prompt investigation of the causes of any observed liver enzyme elevations are recommended to identifypotential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of tofacitinib should be interrupted until this diagnosis has been excluded.
In post-marketing experience, cases of drug hypersensitivity associated with tofacitinib administration have been reported. Allergic reactions included angioedema and urticaria; serious reactions have occurred. If any serious allergic or anaphylactic reaction occurs, tofacitinib should be discontinued immediately.
Treatment with tofacitinib was associated with an increased incidence of lymphopenia compared to placebo. Lymphocyte counts less than 750 cells/mm3 were associated with an increased incidence of serious infections. It is not recommended to initiate or continue tofacitinib treatment in patients with a confirmed lymphocyte count less than 750 cells/mm3. Lymphocytes should be monitored at baseline and every 3 months thereafter. For recommended modifications based on lymphocyte counts.
Treatment with tofacitinib was associated with an increased incidence of neutropenia (less than 2,000 cells/mm3) compared to placebo. It is not recommended to initiate tofacitinib treatment in patients with an ANC less than 1,000 cells/mm3. ANC should be monitored at baseline and after 4 to 8 weeks of treatment and every 3 months thereafter. For recommended modifications based on ANC.
Treatment with tofacitinib has been associated with decreases in haemoglobin levels. It is not recommended to initiate tofacitinib treatment in patients with a haemoglobin value less than 9 g/dL. Haemoglobin should be monitored at baseline and after 4 to 8 weeks of treatment and every 3 months thereafter. For recommended modifications based on haemoglobin level.
Treatment with tofacitinib was associated with increases in lipid parameters such as total cholesterol, lowdensity lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. Assessment of lipid parameters should be performed after 8 weeks following initiation of tofacitinib therapy. Patients should be managed according to clinical guidelines for the management of hyperlipidaemia. Increases in total and LDL cholesterol associated with tofacitinib may be decreased to pretreatment levels with statin therapy.
Prior to initiating tofacitinib, it is recommended that all patients be brought up to date with all immunisations in agreement with current immunisation guidelines. It is recommended that live vaccines not be given concurrently with tofacitinib. The decision to use live vaccines prior to tofacitinib treatment should take into account the pre-existing immunosuppression in a given patient.
Prophylactic zoster vaccination should be considered in accordance with vaccination guidelines. Particular consideration should be given to patients with long standing RA who have previously received two or more biological DMARDs. 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 (VZV). If the history of chickenpox is considered doubtful or unreliable it is recommended to test for antibodies against VZV.
Vaccination with live vaccines should occur at least 2 weeks but preferably 4 weeks prior to initiation of tofacitinib or in accordance with current vaccination guidelines regarding immunomodulatory medicinal products. No data are available on the secondary transmission of infection by live vaccines to patients receiving tofacitinib.
Since tofacitinib is metabolised by CYP3A4, interaction with medicinal products that inhibit or induce CYP3A4 is likely. Tofacitinib exposure is increased when coadministered with potent inhibitors of CYP3A4 (e.g., ketoconazole) or when administration of one or more concomitant medicinal products results in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole)
Tofacitinib exposure is decreased when coadministered with potent CYP inducers (e.g., rifampicin). Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to significantly alter the PK of tofacitinib.
Coadministration with ketoconazole (strong CYP3A4 inhibitor), fluconazole (moderate CYP3A4 and potent CYP2C19inhibitor), tacrolimus (mild CYP3A4 inhibitor) and ciclosporine (moderate CYP3A4 inhibitor) increased tofacitinib AUC, while rifampicin (potent CYP inducer) decreased tofacitinib AUC.
Coadministration of tofacitinib with potent CYP inducers (e.g., rifampicin) may result in a loss of or reduced clinical response. Coadministration of potent inducers of CYP3A4 with tofacitinib is not recommended. Coadministration with ketoconazole and fluconazole increased tofacitinib Cmax, while tacrolimus, ciclosporine and rifampicin decreased tofacitinib Cmax. Concomitant administration with methotrexate 15- 25 mg once weekly had no effect on the PK of tofacitinib in RA patients
Coadministration of tofacitinib did not have an effect on the PK of oral contraceptives, levonorgestrel and ethinylestradiol, in healthy female volunteers.
In RA patients, coadministration of tofacitinib with methotrexate 15-25 mg once weekly decreased the AUC and Cmax of methotrexate by 10% and 13%, respectively. The extent of decrease in methotrexate exposure does not warrant modifications to the individualised dosing of methotrexate.
There are no adequate and well-controlled studies on the use of tofacitinib in pregnant women. Tofacitinib has been shown to be teratogenic in rats and rabbits, and to affect parturition and peri/postnatal development.
As a precautionary measure, the use of tofacitinib during pregnancy is contraindicated.
Contraception to be used in women in childbearing age.
It is not known whether tofacitinib is secreted in human milk. A risk to the breast-fed child cannot be excluded. Tofacitinib was secreted in the milk of lactating rats. As a precautionary measure, the use of tofacitinib during breast-feeding is contraindicated.
Formal studies of the potential effect on human fertility have not been conducted. Tofacitinib impaired female fertility but not male fertility in rats.
Tofacitinib has no or negligible influence on the ability to drive and use machines.
The ADRs listed in the table below are from clinical studies in patients with RA presented by System Organ Class (SOC) and frequency categories, defined using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), or not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
| System organ class | Common= 1/100 to <1/10 | Uncommon= 1/1,000 to <1/100 | Rare= 1/10,000 to <1/1,000 | Very rare <1/10,000 | Not known (cannot be estimated from the available data) |
|---|---|---|---|---|---|
| Infections and infestations | Pneumonia Influenza Herpes zoster Urinary tract infection Sinusitis Bronchitis Nasopharyngitis Pharyngitis | Tuberculosis Diverticulitis Pyelonephritis Cellulitis Herpes simplex Gastroenteritis viral Viral infection | Sepsis Urosepsis Disseminated TB Necrotizing fasciitis Bacteraemia Staphylococcal bacteraemia Pneumocystis jirovecii pneumonia Pneumonia pneumococcal Pneumonia bacterial Encephalitis Atypical mycobacterial infection Cytomegalovirus infection Arthritis bacterial | Tuberculosis of central nervous system Meningitis cryptococcal Mycobacterium avium complex infection | |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Non-melanoma skin cancers | ||||
| Blood and lymphatic system disorders | Anaemia | Leukopenia Lymphopenia Neutropenia | |||
| Immune system disorders | Drug hypersensitivity* Angioedema* Urticaria* | ||||
| Metabolism and nutrition disorders | Dyslipidaemia Hyperlipidaemia Dehydration | ||||
| Psychiatric disorders | Insomnia | ||||
| Nervous system disorders | Headache | Paraesthesia | |||
| Vascular disorders | Hypertension | Venous thromboembolism** | |||
| Respiratory, thoracic and mediastinal disorders | Cough | Dyspnoea Sinus congestion | |||
| Gastrointestinal disorders | Abdominal pain Vomiting Diarrhoea Nausea Gastritis Dyspepsia | ||||
| Hepatobiliary disorders | Hepatic steatosis Hepatic enzyme increased Transaminases increased Liver function test abnormal Gamma glutamyltransferase increased | ||||
| Skin and subcutaneous tissue disorders | Rash | Erythema Pruritus | |||
| Musculoskeletal and connective tissue disorders | Arthralgia | Musculoskeletal pain Joint swelling endonitis | |||
| General disorders and administration site conditions | Pyrexia Oedema peripheral Fatigue | ||||
| Investigations | Blood creatine phosphokinase increased | Blood creatinine increased Blood cholesterol increased Low density lipoprotein increased Weight increased | |||
| Injury, poisoning and procedural complications | Ligament sprain Muscle strain |
*Spontaneous reporting data **Venous thromboembolism includes PE and DVT
Reporting of suspected adverse reactions
Health care professionals, patients/consumers are advised to closely monitor the possibility of the above ADRs associated with the use of the above drugs. If such reactions are encountered, please report to the Hetero either by filling of Suspect Adverse Drug Reactions Reporting Form (form.heteroworld.com) or by Hetero Helpline No.1800-120-8689 and for all India safety cases and complaints, please write to drugsafetyindia@heterodrugs.com
In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. There is no specific antidote for overdose with tofacitinib. Treatment should be symptomatic and supportive.
Pharmacokinetic data up to and including a single dose of 100 mg in healthy volunteers indicate that more than 95% of the administered dose is expected to be eliminated within 24 hours.
Tofacitinib is a potent, selective inhibitor of the JAK family. In enzymatic assays, tofacitinib inhibits JAK1, JAK2, JAK3, and to a lesser extent TyK2. In contrast, tofacitinib has a high degree of selectivity against other kinases in the human genome. In human cells, tofacitinib preferentially inhibits signalling by heterodimeric cytokine receptors that associate with JAK3 and/or JAK1 with functional selectivity over cytokine receptors that signal via pairs of JAK2. Inhibition of JAK1 and JAK3 by tofacitinib attenuates signalling of interleukins (IL-2, -4, -6, -7, -9, -15, -21) and type I and type II interferons, which will result in modulation of the immune and inflammatory response.
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 Tlymphocyte 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.
The PK profile of tofacitinib is characterised by rapid absorption (peak plasma concentrations are reached within 0.5-1 hour), rapid elimination (half-life of ~3 hours) and dose-proportional increases in systemic exposure. Steady state concentrations are achieved in 24-48 hours with negligible accumulation after twice daily administration.
Tofacitinib is well-absorbed, with an oral bioavailability of 74%. Coadministration 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 meal.
After intravenous administration, the volume of distribution is 87 L. Approximately 40% of circulating tofacitinib is bound to plasma proteins. Tofacitinib binds predominantly to albumin and does not appear to bind to α1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma.
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 radiolabelled study, more than 65% of the total circulating radioactivity was accounted for by unchanged active substance, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity. All metabolites have been observed in animal species and are predicted to have less than 10-fold potency than tofacitinib for JAK1/3 inhibition. No evidence of stereo conversion in human samples was detected. The pharmacologic activity of tofacitinib is attributed to the parent molecule. In vitro, tofacitinib is a substrate for MDR1, but not for breast cancer resistance protein (BCRP), OATP1B1/1B3, or OCT1/2.
The enzymatic activity of CYP enzymes is reduced in RA patients due to chronic inflammation. In RA patients, the oral clearance of tofacitinib does not vary with time, indicating that treatment with tofacitinib does not normalise CYP enzyme activity.
Population PK analysis in RA patients indicated that systemic exposure (AUC) of tofacitinib in the extremes of body weight (40 kg, 140 kg) were similar (within 5%) to that of a 70 kg patient. Elderly patients 80 years of age were estimated to have less than 5% higher AUC relative to the mean age of 55 years. Women were estimated to have 7% lower AUC compared to men. The available data have also shown that there are no major differences in tofacitinib AUC between White, Black and Asian patients. An approximate 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 between-subject variability (percentage coefficient of variation) in AUC of tofacitinib is estimated to be approximately 27%.
Subjects with mild (creatinine clearance 50-80 mL/min), moderate (creatinine clearance 30-49 mL/min), and severe (creatinine clearance < 30 mL/min) renal impairment had 37%, 43% and 123% higher AUC, respectively, compared to subjects with normal renal function (see section 4.2). In subjects with end-stage renal disease (ESRD), contribution of dialysis to the total clearance of tofacitinib was relatively small. Following a single dose of 10 mg, mean AUC in subjects with ESRD based on concentrations measured on a non-dialysis day was approximately 40% (90% confidence intervals: 1.5-95%) higher compared to subjects with normal renal function. In clinical trials, tofacitinib was not evaluated in patients with baseline creatinine clearance values (estimated by Cockroft-Gault equation) less than 40 mL/min.
Subjects with mild (Child Pugh A) and moderate (Child Pugh B) hepatic impairment had 3%, and 65% higher AUC, respectively, compared to subjects with normal hepatic function. In clinical trials, tofacitinib was not evaluated in subjects with severe (Child Pugh C) hepatic impairment (see sections 4.2 and 4.4), or in patients screened positive for hepatitis B or C.
Tofacitinib is not an inhibitor or inducer of CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and is not an inhibitor of UGTs (UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7). Tofacitinib is not an inhibitor of MDR1, OATP1B1/1B3, OCT2, OAT1/3, or MRP at clinically meaningful concentrations.
In non-clinical studies, effects were observed on the immune and haematopoietic systems that were attributed to the pharmacological properties (JAK inhibition) of tofacitinib. Secondary effects from immunosuppression, such as bacterial and viral infections and lymphoma were observed at clinically relevant doses. Lymphoma was observed in 3 of 8 adult monkeys at 6 or 3 times the clinical tofacitinib exposure level (unbound AUC in humans at a dose of 5 mg or 10 mg twice daily), and 0 of 14 juvenile monkeys at 5 or 2.5 times the clinical exposure level of 5 mg or 10 mg twice daily. Exposure in monkeys at the no observed adverse effect level (NOAEL) for the lymphomas was approximately 1 or 0.5 times the clinical exposure level of 5 mg or 10 mg twice daily. Other findings at doses exceeding human exposures included effects on the hepatic and gastrointestinal systems.
Tofacitinib is not mutagenic or genotoxic based on the results of a series of in vitro and in vivo tests for gene mutations and chromosomal aberrations.
The carcinogenic potential of tofacitinib was assessed in 6-month rasH2 transgenic mouse carcinogenicity and 2-year rat carcinogenicity studies. Tofacitinib was not carcinogenic in mice at exposures up to 38 or 19 times the clinical exposure level at 5 mg or 10 mg twice daily. Benign testicular interstitial (Leydig) cell tumours were observed in rats: benign Leydig cell tumours in rats are not associated with a risk of Leydig cell tumours in humans. Hibernomas (malignancy of brown adipose tissue) were observed in female rats at exposures greater than or equal to 83 or 41 times the clinical exposure level at 5 mg or 10 mg twice daily. Benign thymomas were observed in female rats at 187 or 94 times the clinical exposure level at 5 mg or 10 mg twice daily.
Tofacitinib was shown to be teratogenic in rats and rabbits, and have effects in rats on female fertility (decreased pregnancy rate; decreases in the numbers of corpora lutea, implantation sites, and viable foetuses; and an increase in early resorptions), parturition, and peri/postnatal development. Tofacitinib had no effects on male fertility, sperm motility or sperm concentration. Tofacitinib was secreted in milk of lactating rats at concentrations approximately 2-fold those in serum from 1 to 8 hours postdose.
Tofacitinib citrate is a white to off-white powder with the following chemical name: (3R,4R)-4-methyl-3- (methyl-7H-pyrrolo [2,3-d]pyrimidin-4-ylamino)-ß-oxo-1piperidinepropanenitrile, 2-hydroxy-1,2,3- propanetricarboxylate (1:1).
The solubility of tofacitinib citrate in water is 2.9 mg/mL.
Tofacitinib citrate has a molecular weight of 504.5 Daltons (or 312.4 Daltons as the tofacitinib free base) and a molecular formula of C16H20N6OC6H8O7. The chemical structure of tofacitinib citrate is: It has the following structural formula:
Advise the patient to read the approved patient labelling (Patient Information).
Serious Infections: Inform patients that tofacitinib may lower the ability of their immune system to fight infections. Advise patients not to start taking tofacitinib if they have an active infection. Instruct patients to contact their healthcare provider immediately during treatment if symptoms suggesting infection appear in order to ensure rapid evaluation and appropriate treatment.
Advise patients that the risk of herpes zoster, some cases of which can be serious, is increased in patients treated with tofacitinib.
Malignancies and Lymphoproliferative Disorders: Inform patients that tofacitinib may increase their risk of certain cancers, and that lymphoma and other cancers have been observed in patients taking tofacitinib. Instruct patients to inform their healthcare provider if they have ever had any type of cancer.
Thrombosis: Advise patients to stop taking tofacitinib and to call their healthcare provider right away if they experience any symptoms of thrombosis (sudden shortness of breath, chest pain worsened with breathing, swelling of leg or arm, leg pain or tenderness, red or discolored skin in the affected leg or arm).
Hypersensitivity: Advise patients to stop taking tofacitinib and to call their healthcare provider right away if they experience any symptoms of allergic reactions while taking tofacitinib.
Important Information on Laboratory Abnormalities: Inform patients that tofacitinib may affect certain lab test results, and that blood tests are required before and during tofacitinib treatment.
Pregnancy: Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their prescriber of a known or suspected pregnancy.
Lactation: Advise women not to breastfeed during treatment with tofacitinib and for at least 18 hours after the last dose of tofacitinib.
Infertility: Advise females of reproductive potential that Tofacitinib may impair fertility. It is not known if this effect is reversible.
JAKURA-5 is a prescription medicine called a Janus kinase (JAK) inhibitor.
Disclaimer: The content mentioned in this website is based on the published literature and is for informational purposes only. Hetero Healthcare makes every effort to present accurate and reliable information, but does not warrant, or assume any legal liability or responsibility for, the accuracy or completeness of any information provided. The product prescribing information complies with drug approval for use in Indian and may not reflect regulatory approvals of other countries. The patient information is not intended to substitute professional advice and services of a qualified healthcare professional. Any advice regarding the management of the medical condition is totally in the discreet of the physician’s knowledge and expertise.