Clindamycin-ratiopharm may be available in the countries listed below.
Clindamycin dihydrogen phosphate (a derivative of Clindamycin) is reported as an ingredient of Clindamycin-ratiopharm in the following countries:
Clindamycin hydrochloride (a derivative of Clindamycin) is reported as an ingredient of Clindamycin-ratiopharm in the following countries:
International Drug Name Search
Oflomac may be available in the countries listed below.
Ofloxacin is reported as an ingredient of Oflomac in the following countries:
International Drug Name Search
Flucloxil may be available in the countries listed below.
Flucloxacillin is reported as an ingredient of Flucloxil in the following countries:
International Drug Name Search
SERIOUS INFECTIONS
Patients treated with Cimzia are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.
Cimzia should be discontinued if a patient develops a serious infection or sepsis.
Reported infections include:
The risks and benefits of treatment with Cimzia should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Cimzia, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].
MALIGNANCY
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which Cimzia is a member [see Warnings and Precautions (5.2)]. Cimzia is not indicated for use in pediatric patients.
Cimzia is indicated for reducing signs and symptoms of Crohn's disease and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy.
Cimzia is indicated for the treatment of adults with moderately to severely active rheumatoid arthritis (RA).
Cimzia is administered by subcutaneous injection. Injection sites should be rotated and injections should not be given into areas where the skin is tender, bruised, red or hard. When a 400 mg dose is needed (given as two subcutaneous injections of 200 mg), injections should occur at separate sites in the thigh or abdomen.
The solution should be carefully inspected visually for particulate matter and discoloration prior to administration. The solution should be a clear colorless to yellow liquid, essentially free from particulates and should not be used if cloudy or if foreign particulate matter is present. Cimzia does not contain preservatives; therefore, unused portions of drug remaining in the syringe or vial should be discarded.
The recommended initial adult dose of Cimzia is 400 mg (given as two subcutaneous injections of 200 mg) initially, and at Weeks 2 and 4. In patients who obtain a clinical response, the recommended maintenance regimen is 400 mg every four weeks.
The recommended dose of Cimzia for adult patients with rheumatoid arthritis is 400 mg (given as two subcutaneous injections of 200 mg) initially and at Weeks 2 and 4, followed by 200 mg every other week. For maintenance dosing, Cimzia 400 mg every 4 weeks can be considered [see Clinical Studies (14.2)].
The lyophilized powder should be prepared and administered by a health care professional. Cimzia is provided in a package that contains everything required to reconstitute and inject the drug as described below. Cimzia should be brought to room temperature before reconstituting to facilitate dissolution.
Reconstitute each lyophilized vial of Cimzia using appropriate aseptic technique, with 1 mL of sterile Water for Injection, USP, and a syringe with a 20 gauge needle. Gently swirl each vial of Cimzia without shaking so that all of the lyophilized powder comes into contact with the sterile Water for Injection. Leave the vials undisturbed to fully reconstitute (this may take as long as 30 minutes). Reconstituted Cimzia has a concentration of approximately 200 mg/mL. Once reconstituted, Cimzia is a clear to opalescent, colorless to pale yellow liquid essentially free from particulates.
Prior to injecting, reconstituted Cimzia should be at room temperature. Do not leave reconstituted Cimzia at room temperature for more than 2 hours prior to administration. Using a new 20 gauge (reconstitution) needle for each vial, withdraw the reconstituted solution into a separate syringe for each vial, so that each syringe contains 1 mL of Cimzia (200 mg of certolizumab pegol). Switch each 20 gauge needle to a 23 gauge (dosing) needle and inject the full contents of each syringe subcutaneously into the thigh or abdomen. Where a 400 mg dose is required, separate sites should be used for each 200 mg injection.
Once reconstituted, Cimzia can be stored in the vials for up to 24 hours at 2 to 8°C (36 to 46 °F) prior to injection. Do not freeze.
After proper training in subcutaneous injection technique, a patient may self-inject with the Cimzia Prefilled Syringe if a physician determines that it is appropriate.
Patients using the Cimzia Prefilled Syringe should be instructed to inject the full amount in the syringe (1 mL), according to the directions provided in the Patient Instructions for Use.
Before initiation of therapy with Cimzia, all patients must be evaluated for both active and inactive (latent) tuberculosis infection. The possibility of undetected latent tuberculosis should be considered in patients who have immigrated from or traveled to countries with a high prevalence of tuberculosis or had close contact with a person with active tuberculosis. Appropriate screening tests (e.g. tuberculin skin test and chest x-ray) should be performed in all patients.
Cimzia may be used as monotherapy or concomitantly with non-biological disease modifying anti-rheumatic drugs (DMARDs). In rheumatoid arthritis clinical studies, patients on Cimzia therapy also took concomitant methotrexate (MTX) with the recommended Cimzia dose of 200 mg every other week. Cimzia should not be used in combination with biological DMARDs or other tumor necrosis factor (TNF) blocker therapy.
None.
(see also Boxed Warning)
Patients treated with Cimzia are at an increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.
Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease.
Treatment with Cimzia should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants (e.g. corticosteroids or methotrexate) may be at a greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients:
Tuberculosis
Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving Cimzia, including patients who have previously received treatment for latent or active tuberculosis. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating Cimzia and periodically during therapy.
Treatment of latent tuberculosis infection prior to therapy with TNF-blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating Cimzia, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG).
Anti-tuberculosis therapy should also be considered prior to initiation of Cimzia 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 having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision of whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
Tuberculosis should be strongly considered in patients who develop a new infection during Cimzia treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.
Monitoring
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Cimzia, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with Cimzia.
Cimzia should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with Cimzia should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated.
Invasive Fungal Infections
For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and risks of antifungal therapy.
In the controlled portions of clinical studies of some TNF blockers, more cases of malignancies have been observed among patients receiving TNF blockers compared to control patients. During controlled and open-labeled portions of Cimzia studies of Crohn's disease and other diseases, malignancies (excluding non-melanoma skin cancer) were observed at a rate (95% confidence interval) of 0.5 (0.4, 0.7) per 100 patient-years among 4,650 Cimzia-treated patients versus a rate of 0.6 (0.1, 1.7) per 100 patient-years among 1,319 placebo-treated patients. The size of the control group and limited duration of the controlled portions of the studies precludes the ability to draw firm conclusions.
Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation of therapy ≤ 18 years of age), of which Cimzia is a member. Approximately half the cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous post-marketing reports.
In the controlled portions of clinical trials of all the TNF blockers, more cases of lymphoma have been observed among patients receiving TNF blockers compared to control patients. In controlled studies of Cimzia for Crohn's disease and other investigational uses, there was one case of lymphoma among 2,657 Cimzia-treated patients and one case of Hodgkin's lymphoma among 1,319 placebo-treated patients.
In the Cimzia RA clinical trials (placebo-controlled and open label) a total of three cases of lymphoma were observed among 2,367 patients. This is approximately 2-fold higher than expected in the general population. Patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma.
Rates in clinical studies for Cimzia cannot be compared to the rates of clinical trials of other TNF blockers and may not predict the rates observed when Cimzia is used in a broader patient population. Patients with Crohn's disease that require chronic exposure to immunosuppressant therapies may be at higher risk than the general population for the development of lymphoma, even in the absence of TNF blocker therapy [see Adverse Reactions (6.1)]. The potential role of TNF blocker therapy in the development of malignancies in adults is not known.
Cases of acute and chronic leukemia have been reported in association with post-marketing TNF-blocker use in RA and other indications. Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.
Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers, including Cimzia. Cimzia has not been formally studied in patients with CHF; however, in clinical studies in patients with CHF with another TNF blocker, worsening congestive heart failure (CHF) and increased mortality due to CHF were observed. Exercise caution in patients with heart failure and monitor them carefully [see Adverse Reactions (6.1)].
The following symptoms that could be compatible with hypersensitivity reactions have been reported rarely following Cimzia administration to patients: angioedema, dyspnea, hypotension, rash, serum sickness, and urticaria. If such reactions occur, discontinue further administration of Cimzia and institute appropriate therapy. There are no data on the risks of using Cimzia in patients who have experienced a severe hypersensitivity reaction towards another TNF blocker; in these patients caution is needed [see Adverse Reactions (6.1)].
Use of TNF blockers, including Cimzia, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation.
Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating Cimzia therapy. Exercise caution in prescribing Cimzia for patients identified as carriers of HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. Patients who are carriers of HBV and require treatment with Cimzia should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy.
In patients who develop HBV reactivation, discontinue Cimzia and initiate effective anti-viral therapy with appropriate supportive treatment. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, exercise caution when considering resumption of Cimzia therapy in this situation and monitor patients closely.
Use of TNF blockers, of which Cimzia is a member, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis, and with peripheral demyelinating disease, including Guillain-Barré syndrome. Exercise caution in considering the use of Cimzia in patients with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders. Rare cases of neurological disorders, including seizure disorder, optic neuritis, and peripheral neuropathy have been reported in patients treated with Cimzia [see Adverse Reactions (6.1)].
Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF blockers. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., leukopenia, pancytopenia, thrombocytopenia) have been infrequently reported with Cimzia [see Adverse Reactions (6.1)]. The causal relationship of these events to Cimzia remains unclear.
Although no high risk group has been identified, exercise caution in patients being treated with Cimzia who have ongoing, or a history of, significant hematologic abnormalities. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on Cimzia. Consider discontinuation of Cimzia therapy in patients with confirmed significant hematologic abnormalities.
Serious infections were seen in clinical studies with concurrent use of anakinra (an interleukin-1 antagonist) and another TNF blocker, etanercept, with no added benefit compared to entanercept alone. A higher risk of serious infections was also observed in combination use of TNF blockers with abatacept and rituximab. Because of the nature of the adverse events seen with this combination therapy, similar toxicities may also result from the use of Cimzia in this combination. Therefore, the use of Cimzia in combination with other biological DMARDs is not recommended [see Drug Interactions (7.1)].
Treatment with Cimzia may result in the formation of autoantibodies and rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with Cimzia, discontinue treatment [see Adverse Reactions (6.1)].
No data are available on the response to vaccinations or the secondary transmission of infection by live vaccines in patients receiving Cimzia. Do not administer live vaccines or attenuated vaccines concurrently with Cimzia.
Since TNF mediates inflammation and modulates cellular immune responses, the possibility exists for TNF blockers, including Cimzia, to affect host defenses against infections and malignancies. The impact of treatment with Cimzia on the development and course of malignancies, as well as active and/or chronic infections, is not fully understood [see Warnings and Precautions (5.1, 5.2, 5.5) and Adverse Reactions (6.1)]. The safety and efficacy of Cimzia in patients with immunosuppression has not been formally evaluated.
The most serious adverse reactions were:
In premarketing controlled trials of all patient populations combined the most common adverse reactions (≥ 8%) were upper respiratory infections (18%), rash (9%) and urinary tract infections (8%).
Adverse Reactions Most Commonly Leading to Discontinuation of Treatment in Premarketing Controlled Trials
The proportion of patients with Crohn's disease who discontinued treatment due to adverse reactions in the controlled clinical studies was 8% for Cimzia and 7% for placebo. The most common adverse reactions leading to the discontinuation of Cimzia (for at least 2 patients and with a higher incidence than placebo) were abdominal pain (0.4% Cimzia, 0.2% placebo), diarrhea (0.4% Cimzia, 0% placebo), and intestinal obstruction (0.4% Cimzia, 0% placebo).
The proportion of patients with rheumatoid arthritis who discontinued treatment due to adverse reactions in the controlled clinical studies was 5% for Cimzia and 2.5% for placebo. The most common adverse reactions leading to discontinuation of Cimzia were tuberculosis infections (0.5%); and pyrexia, urticaria, pneumonia, and rash (0.3%).
Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in 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.
Controlled Studies with Crohn's Disease
The data described below reflect exposure to Cimzia at 400 mg subcutaneous dosing in studies of patients with Crohn's disease. In the safety population in controlled studies, a total of 620 patients with Crohn's disease received Cimzia at a dose of 400 mg, and 614 subjects received placebo (including subjects randomized to placebo in Study CD2 following open label dosing of Cimzia at Weeks 0, 2, 4). In controlled and uncontrolled studies, 1,564 patients received Cimzia at some dose level, of whom 1,350 patients received 400 mg Cimzia. Approximately 55% of subjects were female, 45% were male, and 94% were Caucasian. The majority of patients in the active group were between the ages of 18 and 64.
During controlled clinical studies, the proportion of patients with serious adverse reactions was 10% for Cimzia and 9% for placebo. The most common adverse reactions (occurring in ≥ 5% of Cimzia-treated patients, and with a higher incidence compared to placebo) in controlled clinical studies with Cimzia were upper respiratory infections (e.g. nasopharyngitis, laryngitis, viral infection) in 20% of Cimzia-treated patients and 13% of placebo-treated patients, urinary tract infections (e.g. bladder infection, bacteriuria, cystitis) in 7% of Cimzia-treated patients and in 6% of placebo-treated patients, and arthralgia (6% Cimzia, 4% placebo).
Other Adverse Reactions
The most commonly occurring adverse reactions in controlled trials of Crohn's disease were described above. Other serious or significant adverse reactions reported in controlled and uncontrolled studies in Crohn's disease and other diseases, occurring in patients receiving Cimzia at doses of 400 mg or other doses include:
Blood and lymphatic system disorders: Anemia, leukopenia, lymphadenopathy, pancytopenia, and thrombophilia.
Cardiac disorders: Angina pectoris, arrhythmias, atrial fibrillation, cardiac failure, hypertensive heart disease, myocardial infarction, myocardial ischemia, pericardial effusion, pericarditis, stroke and transient ischemic attack.
Eye disorders: Optic neuritis, retinal hemorrhage, and uveitis.
General disorders and administration site conditions: Bleeding and injection site reactions.
Hepatobiliary disorders: Elevated liver enzymes and hepatitis.
Immune system disorders: Alopecia totalis.
Psychiatric disorders: Anxiety, bipolar disorder, and suicide attempt.
Renal and urinary disorders: Nephrotic syndrome and renal failure.
Reproductive system and breast disorders: Menstrual disorder.
Skin and subcutaneous tissue disorders: Dermatitis, erythema nodosum, and urticaria.
Vascular disorders: Thrombophlebitis, vasculitis.
Controlled Studies with Rheumatoid Arthritis
Cimzia was studied primarily in placebo-controlled trials and in long-term follow-up studies. The data described below reflect the exposure to Cimzia in 2,367 RA patients, including 2,030 exposed for at least 6 months, 1,663 exposed for at least one year and 282 for at least 2 years; and 1,774 in adequate and well-controlled studies. In placebo-controlled studies, the population had a median age of 53 years at entry; approximately 80% were females, 93% were Caucasian and all patients were suffering from active rheumatoid arthritis, with a median disease duration of 6.2 years. Most patients received the recommended dose of Cimzia or higher.
Table 1 summarizes the reactions reported at a rate of at least 3% in patients treated with Cimzia 200 mg every other week compared to placebo (saline formulation), given concomitantly with methotrexate.
| Adverse Reaction (Preferred Term) | Placebo+ MTX* (%) N =324 | Cimzia 200 mg EOW + MTX(%) N =640 |
|---|---|---|
| ||
| Upper respiratory tract infection | 2 | 6 |
| Headache | 4 | 5 |
| Hypertension | 2 | 5 |
| Nasopharyngitis | 1 | 5 |
| Back pain | 1 | 4 |
| Pyrexia | 2 | 3 |
| Pharyngitis | 1 | 3 |
| Rash | 1 | 3 |
| Acute bronchitis | 1 | 3 |
| Fatigue | 2 | 3 |
Hypertensive adverse reactions were observed more frequently in patients receiving Cimzia than in controls. These adverse reactions occurred more frequently among patients with a baseline history of hypertension and among patients receiving concomitant corticosteroids and non-steroidal anti-inflammatory drugs.
Patients receiving Cimzia 400 mg as monotherapy every 4 weeks in rheumatoid arthritis controlled clinical trials had similar adverse reactions to those patients receiving Cimzia 200 mg every other week.
Other Adverse Reactions
Other infrequent adverse reactions (occurring in less than 3% of RA patients) were similar to those seen in Crohn's disease patients.
Infections
The incidence of infections in controlled studies in Crohn's disease was 38% for Cimzia-treated patients and 30% for placebo-treated patients. The infections consisted primarily of upper respiratory infections (20% for Cimzia, 13% for placebo). The incidence of serious infections during the controlled clinical studies was 3% per patient-year for Cimzia-treated patients and 1% for placebo-treated patients. Serious infections observed included bacterial and viral infections, pneumonia, and pyelonephritis.
The incidence of new cases of infections in controlled clinical studies in rheumatoid arthritis was 0.91 per patient-year for all Cimzia-treated patients and 0.72 per patient-year for placebo-treated patients. The infections consisted primarily of upper respiratory tract infections, herpes infections, urinary tract infections, and lower respiratory tract infections. In the controlled rheumatoid arthritis studies, there were more new cases of serious infection adverse reactions in the Cimzia treatment groups, compared to the placebo groups (0.06 per patient-year for all Cimzia doses vs. 0.02 per patient-year for placebo). Rates of serious infections in the 200 mg every other week dose group were 0.06 per patient-year and in the 400 mg every 4 weeks dose group were 0.04 per patient-year. Serious infections included tuberculosis, pneumonia, cellulitis, and pyelonephritis. In the placebo group, no serious infection occurred in more than one subject. There is no evidence of increased risk of infections with continued exposure over time [see Warnings and Precautions (5.1)].
Tuberculosis and Opportunistic Infections
In completed and ongoing global clinical studies in all indications including 5,118 Cimzia-treated patients, the overall rate of tuberculosis is approximately 0.61 per 100 patient-years across all indications.
The majority of cases occurred in countries with high endemic rates of TB. No cases of TB (0/980) have been reported in the US or Canada across all indications. Reports include cases of miliary, lymphatic, peritoneal, as well as pulmonary TB. The median time to onset of TB for all patients exposed to Cimzia across all indications was 345 days. In the studies with Cimzia in RA, there were 36 cases of TB among 2,367 exposed patients, including some fatal cases. Rare cases of opportunistic infections have also been reported in these clinical trials. [see Warnings and Precautions (5.1)].
Malignancies
In clinical studies of Cimzia, the overall incidence rate of malignancies was similar for Cimzia-treated and control patients. For some TNF blockers, more cases of malignancies have been observed among patients receiving those TNF blockers compared to control patients. [see Warnings and Precautions (5.2)]
Heart Failure
In placebo-controlled and open-label rheumatoid arthritis studies, cases of new or worsening heart failure have been reported for Cimzia-treated patients. The majority of these cases were mild to moderate and occurred during the first year of exposure. [see Warnings and Precautions (5.3)].
Autoantibodies
In clinical studies in Crohn's disease, 4% of patients treated with Cimzia and 2% of patients treated with placebo that had negative baseline ANA titers developed positive titers during the studies. One of the 1,564 Crohn's disease patients treated with Cimzia developed symptoms of a lupus-like syndrome.
In clinical trials of TNF blockers, including Cimzia, in patients with RA, some patients have developed ANA. Four patients out of 2,367 patients treated with Cimzia in RA clinical studies developed clinical signs suggestive of a lupus-like syndrome. The impact of long-term treatment with Cimzia on the development of autoimmune diseases is unknown [see Warnings and Precautions (5.9)].
Immunogenicity
Patients were tested at multiple time points for antibodies to certolizumab pegol during Studies CD1 and CD2. The overall percentage of antibody positive patients was 8% in patients continuously exposed to Cimzia, approximately 6% were neutralizing in vitro. No apparent correlation of antibody development to adverse events or efficacy was observed. Patients treated with concomitant immunosuppressants had a lower rate of antibody development than patients not taking immunosuppressants at baseline (3% and 11%, respectively). The following adverse events were reported in Crohn's disease patients who were antibody-positive (N = 100) at an incidence at least 3% higher compared to antibody-negative patients (N = 1,242): abdominal pain, arthralgia, edema peripheral, erythema nodosum, injection site erythema, injection site pain, pain in extremity, and upper respiratory tract infection.
The overall percentage of patients with antibodies to certolizumab pegol detectable on at least one occasion was 7% (105 of 1,509) in the rheumatoid arthritis placebo-controlled trials. Approximately one third (3%, 39 of 1,509) of these patients had antibodies with neutralizing activity in vitro. Patients treated with concomitant immunosuppressants (MTX) had a lower rate of antibody development than patients not taking immunosuppressants at baseline. Patients treated with concomitant immunosuppressant therapy (MTX) in RA-I, RA-II, RA-III had a lower rate of neutralizing antibody formation overall than patients treated with Cimzia monotherapy in RA-IV (2% vs. 8%). Both the loading dose of 400 mg every other week at Weeks 0, 2 and 4 and concomitant use of MTX were associated with reduced immunogenicity.
Antibody formation was associated with lowered drug plasma concentration and reduced efficacy. In patients receiving the recommended Cimzia dosage of 200 mg every other week with concomitant MTX, the ACR20 response was lower among antibody positive patients than among antibody-negative patients (Study RA-I, 48% versus 60%; Study RA-II 35% versus 59%, respectively). In Study RA-III, too few patients developed antibodies to allow for meaningful analysis of ACR20 response by antibody status. In Study RA-IV (monotherapy), the ACR20 response was 33% versus 56%, antibody-positive versus antibody-negative status, respectively. [see Clinical Pharmacology (12.3)]. No association was seen between antibody development and the development of adverse events.
The data reflect the percentage of patients whose test results were considered positive for antibodies to certolizumab pegol in an ELISA, and are highly dependent on the sensitivity and specificity of the assay. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to certolizumab pegol with the incidence of antibodies to other products may be misleading.
Hypersensitivity Reactions
The following symptoms that could be compatible with hypersensitivity reactions have been reported rarely following Cimzia administration to patients: angioedema, dermatitis allergic, dizziness (postural), dyspnea, hot flush, hypotension, injection site reactions, malaise, pyrexia, rash, serum sickness, and (vasovagal) syncope [see Warnings and Precautions (5.4)].
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure.
Vascular disorder: systemic vasculitis has been identified during post-approval use of TNF blockers.
Skin: case of severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and new or worsening psoriasis (all sub-types including pustular and palmoplantar) have been identified during post-approval use of TNF blockers.
An increased risk of serious infections has been seen in clinical studies of other TNF-blocking agents used in combination with anakinra or abatacept, with no added benefit. Formal drug interaction studies have not been performed with rituximab or natalizumab. Because of the nature of the adverse events seen with these combinations with TNF blocker therapy, similar toxicities may also result from the use of Cimzia in these combinations. There is not enough information to assess the safety and efficacy of such combination therapy. Therefore, the use of Cimzia in combination with anakinra, abatacept, rituximab, or natalizumab is not recommended [see Warnings and Precautions (5.8)] .
Do not give live (including attenuated) vaccines concurrently with Cimzia [see Warnings and Precautions (5.10)] .
Interference with certain coagulation assays has been detected in patients treated with Cimzia. Certolizumab pegol may cause erroneously elevated activated partial thromboplastin time (aPTT) assay results in patients without coagulation abnormalities. This effect has been observed with the PTT-Lupus Anticoagulant (LA) test and Standard Target Activated Partial Thromboplastin time (STA-PTT) Automate tests from Diagnostica Stago, and the HemosIL APTT-SP liquid and HemosIL lyophilized silica tests from Instrumentation Laboratories. Other aPTT assays may be affected as well. Interference with thrombin time (TT) and prothrombin time (PT) assays has not been observed. There is no evidence that Cimzia therapy has an effect on in vivo coagulation.
Pregnancy Category B – Because certolizumab pegol does not cross-react with mouse or rat TNFα, reproduction studies were performed in rats using a rodent anti-murine TNFα pegylated Fab' fragment (cTN3 PF) similar to certolizumab pegol. Reproduction studies have been performed in rats at doses up to 100 mg/kg and have revealed no evidence of impaired fertility or harm to the fetus due to cTN3 PF. There are, however, no adequate and well-controlled studies of Cimzia in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Cimzia, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of Cimzia did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Population pharmacokinetic analyses of patients enrolled in Cimzia clinical studies concluded that there was no apparent difference in drug concentration regardless of age. Because there is a higher incidence of infections in the elderly population in general, use caution when treating the elderly with Cimzia [see Warnings and Precautions (5.1)].
The maximum tolerated dose of certolizumab pegol has not been established. Doses of up to 800 mg subcutaneous and 20 mg/kg intravenous have been administered without evidence of dose-limiting toxicities. In cases of overdosage, it is recommended that patients be monitored closely for any adverse reactions or effects, and appropriate symptomatic treatment instituted immediately.
Cimzia (certolizumab pegol) is a TNF blocker. Cimzia is a recombinant, humanized antibody Fab' fragment, with specificity for human tumor necrosis factor alpha (TNFα), conjugated to an approximately 40kDa polyethylene glycol (PEG2MAL40K). The Fab' fragment is manufactured in E. coli and is subsequently subjected to purification and conjugation to PEG2MAL40K, to generate certolizumab pegol. The Fab' fragment is composed of a light chain with 214 amino acids and a heavy chain with 229 amino acids. The molecular weight of certolizumab pegol is approximately 91 kiloDaltons.
Cimzia is supplied as either a sterile, white, lyophilized powder for solution or as a sterile, solution in a single-use prefilled 1 mL glass syringe for subcutaneous injection. After reconstitution of the lyophilized powder with 1 mL sterile Water for Injection, USP, the resulting pH is approximately 5.2. Each single-use vial provides approximately 200 mg certolizumab pegol, 0.9 mg lactic acid, 0.1 mg polysorbate, and 100 mg sucrose.
Each single-use prefilled syringe of Cimzia delivers 200 mg in 1 mL of solution with a pH of approximately 4.7 for subcutaneous use. Each 1 mL syringe of Cimzia contains certolizumab pegol (200 mg), sodium acetate (1.36 mg), sodium chloride (7.31 mg), and Water for Injection, USP.
Cimzia is a clear to opalescent solution that is colorless to pale yellow and essentially free from particulates. No preservatives are present.
Certolizumab pegol binds to human TNFα with a KD of 90pM. TNFα is a key pro-inflammatory cytokine with a central role in inflammatory processes. Certolizumab pegol selectively neutralizes TNFα (IC90 of 4 ng/mL for inhibition of human TNFα in the in vitro L929 murine fibrosarcoma cytotoxicity assay) but does not neutralize lymphotoxin α (TNFβ). Certolizumab pegol cross-reacts poorly with TNF from rodents and rabbits, therefore in vivo efficacy was evaluated using animal models in which human TNFα was the physiologically active molecule.
Certolizumab pegol was shown to neutralize membrane-associated and soluble human TNFα in a dose-dependent manner. Incubation of monocytes with certolizumab pegol resulted in a dose-dependent inhibition of LPS-induced TNFα and IL-1β production in human monocytes.
Certolizumab pegol does not contain a fragment crystallizable (Fc) region, which is normally present in a complete antibody, and therefore does not fix complement or cause antibody-dependent cell-mediated cytotoxicity in vitro. It does not induce apoptosis in vitro in human peripheral blood-derived monocytes or lymphocytes, nor does certolizumab pegol induce neutrophil degranulation.
A tissue reactivity study was carried out ex vivo to evaluate potential cross-reactivity of certolizumab pegol with cryosections of normal human tissues. Certolizumab pegol showed no reactivity with a designated standard panel of normal human tissues.
Biological activities ascribed to TNFα include the upregulation of cellular adhesion molecules and chemokines, upregulation of major histocompatibility complex (MHC) class I and class II molecules, and direct leukocyte activation. TNFα stimulates the production of downstream inflammatory mediators, including interleukin-1, prostaglandins, platelet activating factor, and nitric oxide. Elevated levels of TNFα have been implicated in the pathology of Crohn's disease and rheumatoid arthritis. Certolizumab pegol binds to TNFα, inhibiting its role as a key mediator of inflammation. TNFα is strongly expressed in the bowel wall in areas involved by Crohn's disease and fecal concentrations of TNFα in patients with Crohn's disease have been shown to reflect clinical severity of the disease. After treatment with certolizumab pegol, patients with Crohn's disease demonstrated a decrease in the levels of C-reactive protein (CRP). Increased TNFα levels are found in the synovial fluid of rheumatoid arthritis patients and play an important role in the joint destruction that is a hallmark of this disease.
A total of 126 healthy subjects received doses of up to 800 mg certolizumab pegol subcutaneously (sc) and up to 10 mg/kg intravenously (IV) in four pharmacokinetic studies. Data from these studies demonstrate that single intravenous and subcutaneous doses of certolizumab pegol have predictable dose-related plasma concentrations with a linear relationship between the dose administered and the maximum plasma concentration (Cmax), and the Area Under the certolizumab pegol plasma concentration versus time Curve (AUC). A mean Cmax of approximately 43 to 49 mcg/mL occurred at Week 5 during the initial loading dose period using the recommended dose regimen for the treatment of patient
Diclofenac Tablets 25 mg
Diclofenac Tablets 50 mg
Each enteric-coated tablet contains Diclofenac Sodium 25 mg.
Each enteric-coated tablet contains Diclofenac Sodium 50 mg.
Gastro-resistant tablet
Diclofenac sodium is a non-steroidal agent, with marked analgesic and antiinflammatory properties, used in rheumatoid arthritis; osteoarthritis; osteoarthrosis; low back pain; acute musculo-skeletal disorders and trauma such as periarthritis, tendinitis, tenosynovitis, bursitis sprains, strains and dislocations; relief of pain in fractures; ankylosing spondylitis; acute gout; control of pain and inflammation in orthopaedic, dental and other minor surgery.
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).
Route of administration: Oral
Adults: 75-150 mg daily in two or three divided doses after meals. The recommended maximum daily dose of diclofenac sodium is 150mg.
Diclofenac Tablets 25 mg:
Children (aged 1-12 years): 1-3mg/kg per day in divided doses. Elderly: Although the pharmacokinetics of diclofenac sodium are not impaired to any clinically relevant extent in elderly patients, non-steroidal antiinflammatory drugs should be used with particular caution in such patients who are generally more prone to adverse reactions. In particular it is recommended that the lowest effective dosage be used in frail elderly patients or those with a low body weight (see also Precautions) and the patient should be monitored for GI bleeding during NSAID therapy.
Diclofenac Tablets 50 mg:
Children (aged 1-12 years): These tablets are not recommended for use in children.
Elderly: Although the pharmacokinetics of diclofenac sodium are not impaired to any clinically relevant extent in elderly patients, non-steroidal antiinflammatory drugs should be used with particular caution in such patients who are generally more prone to adverse reactions. In particular it is recommended that the lowest effective dosage be used in frail elderly patients or those with a low body weight (see also Precautions) and the patient should be monitored for GI bleeding during NSAID therapy.
Hypersensitivity to the active substance or any of the excipients.
Patients who have previously shown hypersensitivity reactions (e.g. asthma, angioedema, urticaria or acute rhinitis) to ibuprofen, aspirin or other non-steroidal anti-inflammatory drugs.
Patients with a history of, or active, gastro-intestinal ulcers, bleeding or perforation (two or more distinct episodes of proven ulceration or bleeding).
Severe hepatic, renal and heart failure (see section 4.4 Special warnings and precautions for use).
During the last trimester of pregnancy.
History of gastrointestinal bleeding or perforation, relating to previous NSAID therapy.
Acute porphyria.
Warnings:
In all patients: Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2 Posology and method of administration and GI and cardiovascular risks below).
The use of diclofenac with concomitant NSAIDs including cyclo-oxygenase 2-selective inhibitors should be avoided (see section 4.5 Interactions with other medicaments and other forms of interaction).
Elderly: The elderly have increased frequency of adverse reactions to NSAIDs especially to gastrointestinal bleeding and perforation which may be fatal (see section 4.2 Posology and method of administration).
Gastro-intestinal: Close medical surveillance is imperative in patients with symptoms indicative of gastro-intestinal disorders, with a history suggestive of gastro-intestinal ulceration, with ulcerative colitis or with Crohn's disease as these conditions may be exacerbated (see section 4.8 Undesirable effects).
Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding).
Gastro-intestinal bleeding or ulceration/perforation: Haematemesis, melaena, ulceration or perforation which can be fatal has been reported with all NSAIDs. They can occur at any time during treatment with or without warning symptoms or a previous history of serious GI events. In the rare instances where gastro-intestinal bleeding or ulceration occurs in patients receiving diclofenac sodium the drug should be withdrawn.
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3 Contraindications), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin or other drugs likely to increase gastrointestinal risk (see below and section 4.5 Interactions with other medicaments and other forms of interaction).
Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors (SSRIs) or anti-platelet agents such as aspirin (see section 4.5 Interaction with other medicaments and other forms of interaction).
Hepatic: Close medical surveillance is also imperative in patients suffering from impairment of hepatic function.
Hypersensitivity reactions: As with other non-steroidal anti-inflammatory drugs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug (see Section 4.8 Undesirable effects).
In patients with asthma, seasonal allergic rhinitis, swelling of the nasal mucosa (ie nasal polyps), chronic obstructive pulmonary diseases or chronic infections of the respiratory tract (especially if linked to allergic rhinitis-like symptoms), reactions with NSAIDs such as exacerbation of asthma (so called intolerance to analgesics / analgesics-asthma), Quincke's oedema (angioedema) or urticaria are more frequent than in other patients. Therefore special precautions are recommended in such patients (readiness for emergency). This is also applicable to patients who are allergic to other substances, for example those with skin reactions, pruritis or urticaria.
As with other NSAIDs, diclofenac sodium may mask the signs and symptoms of infection due to its pharmacodynamic properties.
Precautions: Renal: Patients with renal, cardiac or hepatic impairment, a history of hypertension and the elderly, should be kept under surveillance, since the use of NSAIDs may result in deterioration of renal function. The lowest effective dose should be used and renal function monitored.
The importance of prostaglandins in maintaining renal blood flow should be taken into account in patients with impaired cardiac or renal function, those being treated with diuretics or other products that can significantly impact renal function, or those recovering from major surgery. Effects on renal function are usually reversible on withdrawal of diclofenac sodium.
Long-term treatment: All patients who are receiving non-steroidal antiinflammatory agents should be monitored as a precautionary measure e.g. renal function, hepatic function (elevation of liver enzymes may occur) and blood counts. This is particularly important in the elderly.
Hepatic: If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), diclofenac sodium should be discontinued. Hepatitis may occur without prodromal symptoms.
Use of diclofenac sodium in patients with hepatic porphyria may trigger an attack. Use in acute porphyria is contraindicated.
Haematological: Diclofenac sodium may reversibly inhibit platelet aggregation (see anticoagulants in Section 4.5 Interaction with other medicaments and other forms of interactions). Patients with defects of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.
Respiratory disorders: Like other drugs that inhibit prostaglandin synthetase activity, diclofenac sodium and other NSAIDs can precipitate bronchospasm if administered to patients suffering from, or with a previous history of, bronchial asthma.
Cardiovascular and cerebrovascular effects: Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.
Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high doses (150mg daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with diclofenac after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, and smoking).
SLE and mixed connective tissue disease: In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see section 4.8 Undesirable effects).
Dermatological: Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs, including diclofenac (see section 4.8 Undesirable effects). Patients appear to be at the highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Diclofenac should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.
Female fertility: The use of diclofenac sodium may impair female fertility and is not recommended in women attempting to conceive. In women who may have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of diclofenac sodium should be considered.
Lithium: Diclofenac sodium may increase plasma concentrations of lithium.
Anticoagulants: Although clinical investigations do not appear to indicate that diclofenac sodium has an influence on the effect of anticoagulants, there are isolated reports of an increased risk of haemorrhage with the combined use of diclofenac and anticoagulant therapy. Therefore, to be certain that no change in anticoagulant dosage is required, close monitoring of such patients is required. As with other non-steroidal anti-inflammatory agents, diclofenac in a high dose can reversibly inhibit platelet aggregation.
Antidiabetic agents: Clinical studies have shown that diclofenac sodium can be given together with oral antidiabetic agents without influencing their clinical effect. However there have been isolated reports of hypoglycaemic and hyperglycaemic effects which have required adjustment to the dosage of hypoglycaemic agents.
Ciclosporin and tacrolimus: Cases of nephrotoxicity have been reported in patients receiving concomitant ciclosporin and NSAIDs, including diclofenac sodium. Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus. This might be mediated through combined renal anti-prostaglandin effects of both the NSAID and calcineurin inhibitor.
Methotrexate: Cases of serious toxicity have been reported when methotrexate and NSAIDs are given within 24 hours of each other. This interaction is mediated through accumulation of methotrexate resulting from impairment of renal excretion in the presence of the NSAID.
Quinolone antimicrobials: Convulsions may occur due to an interaction between quinolones and NSAIDs. This may occur in patients with or without a previous history of epilepsy or convulsions. Therefore, caution should be exercised when considering the use of a quinolone in patients already receiving an NSAID.
Other NSAIDs including cyclo-oxygenase-2 selective inhibitors and corticosteroids: Co-administration of diclofenac sodium with these agents may increase the risk of gastro-intestinal bleeding or ulceration. Avoid concomitant use of two or more NSAIDs (see section 4.4 Special warnings and precautions for use).
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs):
Increased risk of gastrointestinal bleeding (see section 4.4 Special warnings and precautions for use).
Diuretics: Like other NSAIDs, diclofenac sodium may inhibit the activity of diuretics. Concomitant treatment with potassium-sparing diuretics may be associated with increased serum potassium levels, which should therefore be monitored frequently.
Antihypertensives: Concomitant use of NSAIDs with antihypertensive drugs (i.e. beta-blockers, angiotensin converting enzyme (ACE) inhibitors, diuretics) may cause a decrease in their antihypertensive effect via inhibition of vasodilatory prostaglandin synthesis.
Cardiac glycosides: Concomitant use of cardiac glycosides and NSAIDs in patients may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.
Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effects of mifepristone.
Baclofen: NSAIDs possibly reduce excretion of baclofen (increased risk of toxicity).
Drospirenone: Risk of hyperkalaemia when given with drospirenone (monitor serum potassium during first cycle).
Ketorolac: Increased side effects and haemorrhage if used with NSAIDs.
Penicillamine: Possible increased risk of nephrotoxicity.
Erlotinib, iloprost, pentoxifylline, sibutramine, venlafaxine: Possible increased risk of bleeding.
Phenytoin: NSAIDS possibly enhance effects of phenytoin.
Ritonavir: Plasma concentration of NSAIDs possibly increased by ritonavir.
Zidovudine: Increased risk of haematological toxicity when NSAIDs given with zidovudine.
Pregnancy
Congenital abnormalities have been reported in association with the administration of NSAIDs in man, however, these are low in frequency and do not appear to follow any discernible pattern.
In view of the known effects of NSAIDs on the foetal cardiovascular system (e.g. a premature closure of the ductus arteriosus) and in causing uterine inertia, use in the last trimester of pregnancy is contraindicated. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child (see section 4.3 Contraindications). NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit outweighs the potential risk to foetus. The lowest effective dose should be used and duration kept as short as possible.
Lactation
Following doses of 50mg enteric coated tablets every 8 hours, traces of active substance have been detected in breast milk, but in quantities so small that no adverse effects on the breast fed infant are to be expected.
NSAIDs should if possible be avoided when breast-feeding.
See section 4.4 Special warnings and precautions for use, regarding female fertility.
Patients who experience visual disturbances, dizziness, drowsiness, fatigue or other central nervous system disturbances while taking NSAIDs should refrain from driving or operating machinery.
Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: common (
The following undesirable effects include those reported with diclofenac gastro-resistant tablets and/or other pharmaceutical forms of diclofenac, with either short-term or long-term use.
Blood and lymphatic system disorders
Very rare: Thrombocytopenia, leukopenia, anaemia (including haemolytic and aplastic anaemia), agranulocytosis.
Immune system disorders
Rare: Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock).
Very rare: Angioneurotic oedema (including face oedema).
Psychiatric disorders
Very rare: Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder/reactions, confusion, hallucinations.
Nervous system disorders
Common: Headache, dizziness.
Rare: Somnolence, drowsiness, tiredness, hypotension.
Very rare: Paraesthesia, memory impairment/disturbance, convulsion, anxiety, tremor, taste disturbances, cerebrovascular accident, disturbances of sensation, taste disturbances, malaise, aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus and mixed tissue disease) with symptoms such as fever, stiff neck, headache, nausea and vomiting.
Eye disorders
Very rare: Visual disturbance, vision blurred, diplopia, optic neuritis.
Ear and labyrinth disorders
Common: Vertigo.
Very rare: Tinnitus, hearing impaired.
Cardiac disorders
Very rare: Palpitations, chest pain, cardiac failure/congestive heart failure, myocardial infarction.
Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high doses (150 mg daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events, for example, myocardial infarction or stroke (see section 4.4 Special warnings and special precautions for use).
Vascular disorders
Very rare: Hypertension, vasculitis.
Respiratory, thoracic and mediastinal disorders
Rare: Asthma (including dyspnoea), alveolitis, pulmonary eosinophilia.
Very rare: Pneumonitis.
Aggravated asthma or bronchospasm have also been reported.
Gastrointestinal disorders
Common: Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain or cramps, flatulence, anorexia.
Rare: Gastritis, gastrointestinal haemorrhage or bleeding, haematemesis, diarrhoea haemorrhagic/bloody, melaena, gastrointestinal ulcer, with or without bleeding or perforation (sometimes fatal, particularly in the elderly).
Very rare: Lower gut disorders such as colitis (including colonic damage, non specific haemorrhagic colitis/ haemorrhagic colitis and exacerbation of ulcerative colitis or Crohn's disease/Crohn's proctocolitis), constipation, stomatitis/aphthous stomatitis, glossitis, oesophageal disorder/lesions, diaphragm-like intestinal strictures/stricture formation, pancreatitis.
Hepatobiliary disorders
Common: Transaminases (serum aminotransferase enzymes) increased (eg AST, ALT).
Rare: Hepatitis, jaundice, liver disorder.
Very rare: Fulminant hepatitis.
Skin and subcutaneous tissue disorders.
Common: Rash, skin eruptions.
Rare: Urticaria.
Very rare: Bullous eruptions/dermatoses, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis/acute toxic epidermolysis (Lyell's syndrome), dermatitis exfoliative (erythroderma), loss of hair, photosensitivity reactions, purpura, allergic purpura, pruritus.
Renal and urinary disorders
Rare: Interstitial fibrosis has been reported with NSAIDs and may lead to renal failure.
Very rare: Acute renal failure or insufficiency, urinary abnormalities (eg haematuria, proteinuria), nephrotic syndrome, interstitial nephritis, renal papillary necrosis.
General disorders and administration site conditions
Rare: Oedema.
Very rare: Impotence.
Symptoms:
Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, tinnitus, fainting, occasionally, convulsions. In rare cases of significant poisoning acute renal failure and liver damage are possible.
Therapeutic measures:
Patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered.
Alternatively, in adults gastric lavage should be considered within one hour of ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical condition.
Diclofenac is a non-steroidal agent with marked analgesic and anti-inflammatory properties. It is also an inhibitor of prostaglandin synthetase.
Diclofenac sodium is rapidly absorbed from the gut and is subject to first-pass metabolism. Tablets give plasma peak concentrations after 1-4 hours. It is 99.7% protein bound and has a plasma half-life of 1-2 hours. About 60% of the administered dose is excreted via the kidneys in the form of metabolites and only less than 1% in the unchanged form. The rest of the dose is excreted via the bile in metabolised form.
None provided.
Diclofenac Tablets 25 mg:
Core ingredients:
Sodium starch glycollate BP
Microcrystalline cellulose BP
Lactose BP
Starch maize BP
Magnesium stearate BP
Purified talc BP
Coating ingredients:
Cellulose acetate phthalate BP
Opadry Yellow No. 518 (E171, E104, E110 and E132).
Diclofenac Tablets 50 mg:
Core ingredients:
Povidone K25 BP
Starch maize BP
Lactose BP
Magnesium stearate BP
Purified talc BP
Coating ingredients:
Cellulose acetate phthalate BP
Opadry Butterscotch No. 519 (E171, E104, E172 and E132)
See section 4.5
2 years.
Store below 25°C and protect from moisture.
PVC/foil blisters containing 28, 50, 84 and 100 tablets. Securitainer with snap cap containing 50 and 100 tablets. Amber glass bottle with plastic screwcap containing 50 tablets.
None.
Sandoz Ltd
Woolmer Way
Bordon
Hampshire
GU35 9QE
United Kingdom
PL 04416/0361
PL 04416/0362
08 December 1999/16 March 2009
03/2009
Razene may be available in the countries listed below.
Cetirizine dihydrochloride (a derivative of Cetirizine) is reported as an ingredient of Razene in the following countries:
International Drug Name Search
Momiaron may be available in the countries listed below.
Famotidine is reported as an ingredient of Momiaron in the following countries:
International Drug Name Search
Iverquantel may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Ivermectin is reported as an ingredient of Iverquantel in the following countries:
Praziquantel is reported as an ingredient of Iverquantel in the following countries:
International Drug Name Search
Zomig 5 mg Nasal Spray
zolmitriptan
Zomig Nasal contains zolmitriptan and belongs to a group of medicines called triptans.
Zomig Nasal is used to treat migraine headache.
Do not use Zomig Nasal if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before using Zomig Nasal.
Before you use Zomig Nasal, tell your doctor if:
If you go into hospital tell the medical staff you are taking Zomig Nasal.
Zomig Nasal is not recommended for people aged under 18 years or over 65.
As with other migraine treatments, using too much Zomig Nasal can cause daily headaches or can make your migraine headaches worse. Ask your doctor if you think that this is the case for you. You may need to stop using Zomig Nasal to correct the problem.
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes herbal medicines and medicines you buy without prescription.
In particular, tell your doctor if you are taking any of the following medicines:
Medicines for migraine:
Medicines for depression:
Other medicines:
You should not take the herbal remedy St. John's wort (Hypericum perforatum) at the same time as this medicine. If you already take a St. John's wort preparation, stop taking the St. John's wort and mention this to your doctor at your next visit.
You can take Zomig Nasal with or without food. It does not affect the way that Zomig Nasal works.
Zomig Nasal comes in a ready-to-use spray unit. Each unit contains 5 mg of zolmitriptan. Each unit is for single use and gives only one dose.
Always use Zomig Nasal exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.
You can use Zomig Nasal as soon as a migraine headache starts. You can also use it once an attack is underway.
If the nasal spray did not give you enough help with your migraine, tell your doctor. Your doctor may change your treatment.
Do not use more than the dose prescribed for you.
Please read these instructions before using Zomig Nasal.
Do not press the plunger until you have put the nozzle in your nostril or you will lose the dose.
If you have taken more Zomig Nasal than prescribed by your doctor, tell your doctor or go to the nearest hospital straight away. Take the Zomig Nasal medicine with you.
Like all medicines, Zomig Nasal can cause side effects, although not everybody gets them. Some of the symptoms below could be part of the migraine attack itself.
Rare (affects less than 1 in 1,000 people)
Very rare (affects less than 1 in 10,000 people)
Other possible side effects:
Very common (affects more than 1 in 10 people):
This is usually mild and goes away after a short time.
Common (affects less than 1 in 10 people):
These are usually mild and go away after a short time.
Uncommon (affects less than 1 in 100 people):
Do not be concerned by this list of possible side effects. You may not get any of them. If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
The active ingredient is zolmitriptan. Zomig 5 mg Nasal Spray contains 5 mg zolmitriptan in each dose. The other ingredients are: citric acid, disodium phosphate and purified water.
Zomig may also be available as film-coated tablets 2.5 mg and 5 mg and orodispersible tablets 2.5 mg and 5 mg.
The Marketing Authorisation for Zomig 5 mg Nasal Spray is held by
Zomig 5 mg Nasal Spray is manufactured by
To listen to or request a copy of this leaflet in Braille, large print or audio please call, free of charge:
0800 198 5000 (UK only)
Please be ready to give the following information:
Product Name Zomig 5 mg Nasal Spray
Reference number 17901/0095
This is a service provided by the Royal National Institute of Blind People.
Leaflet prepared: July 2008
© AstraZeneca 2008
Zomig is a trade mark of the AstraZeneca group of companies.
You can also get support and information about migraine from
CNS 07 0216a
P023373
