Mabthera 100mg and 500mg concentrate for solution for infusion

1. Name Of The Medicinal Product

MabThera 100 mg concentrate for solution for infusion

MabThera 500 mg concentrate for solution for infusion

2. Qualitative And Quantitative Composition

Each ml contains 10 mg of rituximab.

100mg - Each single-use vial containing 100 mg of Rituximab.

500mg- Each single-use vial containing 500 mg of Rituximab.

Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody representing a glycosylated immunoglobulin with human IgG1 constant regions and murine light-chain and heavy-chain variable region sequences. The antibody is produced by mammalian (Chinese hamster ovary) cell suspension culture and purified by affinity chromatography and ion exchange, including specific viral inactivation and removal procedures.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Concentrate for solution for infusion.

Clear, colourless liquid.

4. Clinical Particulars

4.1 Therapeutic Indications

MabThera is indicated in adults for the following indications:

Non-Hodgkin's lymphoma (NHL)

MabThera is indicated for the treatment of previously untreated patients with stage III-IV follicular lymphoma in combination with chemotherapy.

MabThera maintenance therapy is indicated for the treatment of follicular lymphoma patients responding to induction therapy.

MabThera monotherapy is indicated for treatment of patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy.

MabThera is indicated for the treatment of patients with CD20 positive diffuse large B cell non-Hodgkin's lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy.

Chronic lymphocytic leukaemia (CLL)

MabThera in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukaemia. Only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies including MabThera or patients refractory to previous MabThera plus chemotherapy.

See section 5.1 for further information.

Rheumatoid arthritis

MabThera in combination with methotrexate is indicated for the treatment of adult patients with severe active rheumatoid arthritis who have had an inadequate response or intolerance to other disease-modifying anti-rheumatic drugs (DMARD) including one or more tumour necrosis factor (TNF) inhibitor therapies.

MabThera has been shown to reduce the rate of progression of joint damage as measured by x-ray and to improve physical function, when given in combination with methotrexate.

4.2 Posology And Method Of Administration

MabThera infusions should be administered under the close supervision of an experienced physician, and in an environment where full resuscitation facilities are immediately available.

Posology

Non-Hodgkin's lymphoma

Dosage adjustments during treatment

No dose reductions of MabThera are recommended. When MabThera is given in combination with chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied.

Follicular non-Hodgkin's lymphoma

Combination therapy

The recommended dose of MabThera in combination with chemotherapy for induction treatment of previously untreated or relapsed/ refractory patients with follicular lymphoma is: 375 mg/m² body surface area per cycle, for up to 8 cycles.

MabThera should be administered on day 1 of each chemotherapy cycle, after intravenous administration of the glucocorticoid component of the chemotherapy if applicable.

Maintenance therapy

Previously untreated follicular lymphoma

The recommended dose of MabThera used as a maintenance treatment for patients with previously untreated follicular lymphoma who have responded to induction treatment is: 375 mg/m² body surface area once every 2 months (starting 2 months after the last dose of induction therapy) until disease progression or for a maximum period of two years.

Relapsed/refractory follicular lymphoma

The recommended dose of MabThera used as a maintenance treatment for patients with relapsed/refractory follicular lymphoma who have responded to induction treatment is: 375 mg/m² body surface area once every 3 months (starting 3 months after the last dose of induction therapy) until disease progression or for a maximum period of two years.

Monotherapy

Relapsed/refractory follicular lymphoma

The recommended dose of MabThera monotherapy used as induction treatment for adult patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy is: 375 mg/m² body surface area, administered as an intravenous infusion once weekly for four weeks.

For retreatment with MabThera monotherapy for patients who have responded to previous treatment with MabThera monotherapy for relapsed/refractory follicular lymphoma, the recommended dose is: 375 mg/m² body surface area, administered as an intravenous infusion once weekly for four weeks (see section 5.1).

Diffuse large B cell non-Hodgkin's lymphoma

MabThera should be used in combination with CHOP chemotherapy. The recommended dosage is 375 mg/m² body surface area, administered on day 1 of each chemotherapy cycle for 8 cycles after intravenous infusion of the glucocorticoid component of CHOP. Safety and efficacy of MabThera have not been established in combination with other chemotherapies in diffuse large B cell non-Hodgkin's lymphoma.

Chronic lymphocytic leukaemia

Prophylaxis with adequate hydration and administration of uricostatics starting 48 hours prior to start of therapy is recommended for CLL patients to reduce the risk of tumour lysis syndrome. For CLL patients whose lymphocyte counts are> 25 x 10⁹/L it is recommended to administer prednisone/prednisolone 100 mg intravenous shortly before infusion with MabThera to decrease the rate and severity of acute infusion reactions and/or cytokine release syndrome.

The recommended dosage of MabThera in combination with chemotherapy for previously untreated and relapsed/refractory patients is 375 mg/m² body surface area administered on day 0 of the first treatment cycle followed by 500 mg/m² body surface area administered on day 1 of each subsequent cycle for 6 cycles in total. The chemotherapy should be given after MabThera infusion.

Rheumatoid arthritis

Patients treated with MabThera must be given the patient alert card with each infusion (see Annex IIIA – Labelling).

A course of MabThera consists of two 1000 mg intravenous infusions. The recommended dosage of MabThera is 1000 mg by intravenous infusion followed by a second 1000 mg intravenous infusion two weeks later.

The need for further courses should be evaluated 24 weeks following the previous course. Retreatment should be given at that time if residual disease activity remains, otherwise retreatment should be delayed until disease activity returns.

Available data suggest that clinical response is usually achieved within 16 - 24 weeks of an initial treatment course. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within this time period.

Patients should receive treatment with 100 mg intravenous methylprednisolone to be completed 30 minutes prior to MabThera infusions to decrease the incidence and severity of infusion related reactions (see method of administration).

First infusion of each course

The recommended initial rate for infusion is 50 mg/hr; after the first 30 minutes, it can be escalated in 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr.

Second infusion of each course

Subsequent doses of MabThera can be infused at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30 minutes intervals, to a maximum of 400 mg/hr.

Special populations

Paediatric use

The safety and efficacy of MabThera in children has not been established.

Elderly

No dose adjustment is required in elderly patients (aged >65 years).

Method of administration

Premedication with glucocorticoids should be considered if MabThera is not given in combination with glucocorticoid-containing chemotherapy for treatment of non-Hodgkin's lymphoma and chronic lymphocytic leukaemia.

Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and diphenhydramine, should always be administered before each infusion of MabThera.

First infusion

The recommended initial rate for infusion is 50 mg/hr; after the first 30 minutes, it can be escalated in 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr.

Subsequent infusions

Subsequent doses of MabThera can be infused at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30 minutes intervals, to a maximum of 400 mg/hr.

The prepared MabThera solution should be administered as an intravenous infusion through a dedicated line. It should not be administered as an intravenous push or bolus.

Patients should be closely monitored for the onset of cytokine release syndrome (see section 4.4). Patients who develop evidence of severe reactions, especially severe dyspnoea, bronchospasm or hypoxia should have the infusion interrupted immediately. Patients with non-Hodgkin's lymphoma should then be evaluated for evidence of tumour lysis syndrome including appropriate laboratory tests and, for pulmonary infiltration, with a chest x-ray. In all patients, the infusion should not be restarted until complete resolution of all symptoms, and normalisation of laboratory values and chest x-ray findings. At this time, the infusion can be initially resumed at not more than one-half the previous rate. If the same severe adverse reactions occur for a second time, the decision to stop the treatment should be seriously considered on a case by case basis.

Mild or moderate infusion-related reactions (section 4.8) usually respond to a reduction in the rate of infusion. The infusion rate may be increased upon improvement of symptoms.

4.3 Contraindications

Contraindications for use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia

Hypersensitivity to the active substance or to any of the excipients or to murine proteins.

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state

Contraindications for use in rheumatoid arthritis

Hypersensitivity to the active substance or to any of the excipients or to murine proteins.

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state

Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease (see section 4.4 regarding other cardiovascular diseases).

4.4 Special Warnings And Precautions For Use

Progressive multifocal leukoencephalopathy

All patients treated with MabThera for rheumatoid arthritis must be given the patient alert card with each infusion (see end of Annex IIIA - Labelling). The alert card contains important safety information for patients regarding potential increased risk of infections, including progressive multifocal leukoencephalopathy (PML).

Use of MabThera maybe associated with an increased risk of PML. Patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. The clinician should evaluate the patient to determine if the symptoms are indicative of neurological dysfunction, and if so, whether these symptoms are possibly suggestive of PML. Consultation with a Neurologist should be considered as clinically indicated.

If any doubt exists, further evaluation, including MRI scan preferably with contrast, CSF testing for JC Viral DNA and repeat neurological assessments, should be considered.

The physician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g. cognitive, neurological or psychiatric symptoms). Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of.

If a patient develops PML, the dosing of MabThera must be permanently discontinued.

Following reconstitution of the immune system in immunocompromised patients with PML, stabilisation or improved outcome has been seen. It remains unknown if early detection of PML and suspension of MabThera therapy may lead to similar stabilisation or improved outcome.

Non-Hodgkin's lymphoma and chronic lymphocytic leukaemia

Infusion reactions

Patients with a high tumour burden or with a high number (⁹/l) of circulating malignant cells such as patients with CLL , who may be at higher risk of especially severe cytokine release syndrome, should only be treated with extreme caution. These patients should be very closely monitored throughout the first infusion. Consideration should be given to the use of a reduced infusion rate for the first infusion in these patients or a split dosing over two days during the first cycle and any subsequent cycles if the lymphocyte count is still >25 x 10⁹/L.

Severe cytokine release syndrome is characterised by severe dyspnea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This syndrome may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, hyperphosphaetemia, acute renal failure, elevated lactate dehydrogenase (LDH) and may be associated with acute respiratory failure and death. The acute respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest x-ray. The syndrome frequently manifests itself within one or two hours of initiating the first infusion. Patients with a history of pulmonary insufficiency or those with pulmonary tumour infiltration may be at greater risk of poor outcome and should be treated with increased caution. Patients who develop severe cytokine release syndrome should have their infusion interrupted immediately (see section 4.2) and should receive aggressive symptomatic treatment. Since initial improvement of clinical symptoms may be followed by deterioration, these patients should be closely monitored until tumour lysis syndrome and pulmonary infiltration have been resolved or ruled out. Further treatment of patients after complete resolution of signs and symptoms has rarely resulted in repeated severe cytokine release syndrome.

Infusion related adverse reactions of all kinds have been observed in 77% of patients treated with MabThera (including cytokine release syndrome accompanied by hypotension and bronchospasm in 10 % of patients) see section 4.8. These symptoms are usually reversible with interruption of MabThera infusion and administration of an anti-pyretic, an antihistaminic, and, occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Please see cytokine release syndrome above for severe reactions.

Anaphylactic and other hypersensitivity reactions have been reported following the intravenous administration of proteins to patients. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes after starting infusion. Medicinal products for the treatment of hypersensitivity reactions, e.g., epinephrine (adrenaline), antihistamines and glucocorticooids, should be available for immediate use in the event of an allergic reaction during administration of MabThera. Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of the cytokine release syndrome (described above). Reactions attributed to hypersensitivity have been reported less frequently than those attributed to cytokine release.

Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia.

Since hypotension may occur during MabThera infusion, consideration should be given to withholding anti-hypertensive medicines 12 hours prior to the MabThera infusion.

Cardiac disorders

Angina pectoris, or cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or myocardial infarction have occurred in patients treated with MabThera. Therefore patients with a history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely.

Haematological toxicities

Although MabThera is not myelosuppressive in monotherapy, caution should be exercised when considering treatment of patients with neutrophils < 1.5 x 10⁹/l and/or platelet counts < 75 x 10⁹/l as clinical experience in this population is limited. MabThera has been used in 21 patients who underwent autologous bone marrow transplantation and other risk groups with a presumable reduced bone marrow function without inducing myelotoxicity.

Regular full blood counts, including neutrophil and platelet counts, should be performed during MabThera therapy.

Infections

Serious infections, including fatalities, can occur during therapy with MabThera (see section 4.8). MabThera should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections, see section 4.3).

Physicians should exercise caution when considering the use of MabThera in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection (see section 4.8).

Cases of hepatitis B reactivation have been reported in subjects receiving MabThera including fulminant hepatitis with fatal outcome. The majority of these subjects were also exposed to cytotoxic chemotherapy. Limited information from one study in relapsed/refractory CLL patients suggest that MabThera treatment may also worsen the outcome of primary hepatitis B infections. Hepatitis B virus (HBV) screening should be considered for high risk patients before initiation of treatment with MabThera. Carriers of hepatitis B and patients with a history of hepatitis B should be closely monitored for clinical and laboratory signs of active HBV infection during and for several months (up to seven) following MabThera therapy.

Very rare cases of progressive multifocal leukoencephalopathy (PML) have been reported during post-marketing use of MabThera in NHL and CLL (see section 4.8). The majority of patients had received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant.

The safety of immunization with live viral vaccines, following MabThera therapy has not been studied for NHL and CLL patients and vaccination with live virus vaccines is not recommended. Patients treated with MabThera may receive non-live vaccinations. However with non-live vaccines response rates may be reduced. In a non-randomized study, patients with relapsed low-grade NHL who received MabThera monotherapy when compared to healthy untreated controls had a lower rate of response to vaccination with tetanus recall antigen (16% vs. 81%) and Keyhole Limpet Haemocyanin (KLH) neoantigen (4% vs. 69% when assessed for >2-fold increase in antibody titer). For CLL patients similar results are assumable considering similarities between both diseases but that has not been investigated in clinical trials.

Mean pre-therapeutic antibody titers against a panel of antigens (Streptococcus pneumoniae, influenza A, mumps, rubella, varicella) were maintained for at least 6 months after treatment with MabThera

Rheumatoid arthritis

Methotrexate (MTX) naïve populations

The use of MabThera is not recommended in MTX-naïve patients since a favourable benefit risk relationship has not been established.

Infusion related reactions

MabThera is associated with infusion related reactions (IRR), which may be related to release of cytokines and/or other chemical mediators. Premedication with intravenous glucocorticoid significantly reduced the incidence and severity of these events and should be administered prior to MabThera treatment (see section 4.2 and section 4.8).

The most common symptoms were allergic reactions like headache, pruritus, throat irritation, flushing, rash, urticaria, hypertension, and pyrexia. In general, the proportion of patients experiencing any infusion reaction was higher following the first infusion than following the second infusion of any treatment course. The incidence of IRR decreased with subsequent courses. The reactions reported were usually reversible with a reduction in rate, or interruption, of MabThera infusion and administration of an anti-pyretic, an antihistamine, and, occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. In most cases, the infusion can be resumed at a 50 % reduction in rate (e.g. from 100 mg/h to 50 mg/h) when symptoms have completely resolved.

Medicinal products for the treatment of hypersensitivity reactions, e.g., epinephrine (adrenaline), antihistamines and glucocorticoids, should be available for immediate use in the event of an allergic reaction during administration of MabThera.

There are no data on the safety of MabThera in patients with moderate heart failure (NYHA class III) or severe, uncontrolled cardiovascular disease. In patients treated with MabThera, the occurrence of pre-existing ischemic cardiac conditions becoming symptomatic, such as angina pectoris, has been observed, as well as atrial fibrillation and flutter. Therefore, in patients with a known cardiac history, the risk of cardiovascular complications resulting from infusion reactions should be considered before treatment with MabThera and patients closely monitored during administration. Since hypotension may occur during MabThera infusion, consideration should be given to withholding anti-hypertensive medications 12 hours prior to the MabThera infusion.

Infections

Serious infections, including fatalities, can occur during therapy with MabThera (see section 4.8). MabThera should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections, see section 4.3) or severely immunocompromised patients (e.g. where levels of CD4 or CD8 are very low). Physicians should exercise caution when considering the use of MabThera in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection, e.g. hypogammaglobulinaemia (see section 4.8). It is recommended that immunoglobulin levels are determined prior to initiating treatment with MabThera.

Patients reporting signs and symptoms of infection following MabThera therapy should be promptly evaluated and treated appropriately. Before giving a subsequent course of MabThera treatment, patients should be re-evaluated for any potential risk for infections.

Very rare cases of fatal progressive multifocal leukoencephalopathy (PML) have been reported following use of MabThera for the treatment of rheumatoid arthritis and autoimmune diseases including Systemic Lupus Erythematosus (SLE) and Vasculitis.

In patients with non-Hodgkin's lymphoma receiving rituximab in combination with cytotoxic chemotherapy, cases of fatal hepatitis B reactivation have been reported (see non-Hodgkin's lymphoma). Reactivation of hepatitis B infection has also been very rarely reported in RA patients receiving MabThera.

Immunization

Physicians should review the patient's vaccination status and follow current immunization guidelines prior to MabThera therapy. Vaccination should be completed at least 4 weeks prior to first administration of MabThera.

The safety of immunization with live viral vaccines following MabThera therapy has not been studied. Therefore vaccination with live virus vaccines is not recommended whilst on MabThera or whilst peripherally B cell depleted.

Patients treated with MabThera may receive non-live vaccinations. However, response rates to non-live vaccines may be reduced. In a randomized study, patients with RA treated with MabThera and methotrexate had comparable response rates to tetanus recall antigen (39% vs. 42%), reduced rates to pneumococcal polysaccharide vaccine (43% vs. 82% to at least 2 pneumococcal antibody serotypes), and KLH neoantigen (47% vs. 93%), when given 6 months after MabThera as compared to patients only receiving methotrexate. Should non-live vaccinations be required whilst receiving MabThera therapy, these should be completed at least 4 weeks prior to commencing the next course of MabThera.

In the overall experience of MabThera repeat treatment over one year, the proportions of patients with positive antibody titers against S. pneumoniae, influenza, mumps, rubella, varicella and tetanus toxoid were generally similar to the proportions at baseline.

Concomitant/sequential use of other DMARDs

The concomitant use of MabThera and antirheumatic therapies other than those specified under the rheumatoid arthritis indication and posology is not recommended.

There are limited data from clinical trials to fully assess the safety of the sequential use of other DMARDs (including TNF inhibitors and other biologics) following MabThera (see section 4.5). The available data indicate that the rate of clinically relevant infection is unchanged when such therapies are used in patients previously treated with MabThera, however patients should be closely observed for signs of infection if biologic agents and/or DMARDs are used following MabThera therapy.

Malignancy

Immunomodulatory drugs may increase the risk of malignancy. On the basis of limited experience with MabThera in rheumatoid arthritis patients (see section 4.8) the present data do not seem to suggest any increased risk of malignancy. However, the possible risk for the development of solid tumours cannot be excluded at this time.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Currently, there are limited data on possible drug interactions with MabThera.

In CLL patients, co-administration with MabThera did not appear to have an effect on the pharmacokinetics of fludarabine or cyclophosphamide. In addition, there was no apparent effect of fludarabine and cyclophosphamide on the pharmacokinetics of rituximab.

Co-administration with methotrexate had no effect on the pharmacokinetics of MabThera in rheumatoid arthritis patients.

Patients with human anti-mouse antibody or human anti-chimeric antibody (HAMA/HACA) titres may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.

In patients with rheumatoid arthritis, 283 patients received subsequent therapy with a biologic DMARD following MabThera. In these patients the rate of clinically relevant infection while on MabThera was 6.01 per 100 patient years compared to 4.97 per 100 patient years following treatment with the biologic DMARD.

4.6 Pregnancy And Lactation

Pregnancy

IgG immunoglobulins are known to cross the placental barrier.

B cell levels in human neonates following maternal exposure to MabThera have not been studied in clinical trials. There are no adequate and well-controlled data from studies in pregnant women, however transient B-cell depletion and lymphocytopenia have been reported in some infants born to mothers exposed to rituximab during pregnancy. For these reasons MabThera should not be administered to pregnant women unless the possible benefit outweighs the potential risk.

Due to the long retention time of rituximab in B cell depleted patients, women of childbearing potential should use effective contraceptive methods during treatment and for 12 months following MabThera therapy.

Developmental toxicity studies performed in cynomolgus monkeys revealed no evidence of embryotoxicity in utero. New born offspring of maternal animals exposed to MabThera were noted to have depleted B cell populations during the post natal phase.

Lactation

Whether rituximab is excreted in human milk is not known. However, because maternal IgG is excreted in human milk, and rituximab was detectable in milk from lactating monkeys, women should not breastfeed while treated with MabThera and for 12 months following MabThera treatment.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects of MabThera on the ability to drive and use machines have been performed, although the pharmacological activity and adverse events reported to date do not indicate that such an effect is likely.

4.8 Undesirable Effects

Experience from non-Hodgkin's lymphoma and chronic lymphocytic leukaemia

The overall safety profile of MabThera in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia is based on data from patients from clinical trials and from post-marketing surveillance. These patients were treated either with MabThera monotherapy (as induction treatment or maintenance treatment following induction treatment) or in combination with chemotherapy.

The most frequently observed adverse drug reactions (ADRs) in patients receiving MabThera were infusion-related reactions which occurred in the majority of patients during the first infusion. The incidence of infusion-related symptoms decreases substantially with subsequent infusions and is less than 1 % after eight doses of MabThera.

Infectious events (predominantly bacterial and viral) occurred in approximately 30-55 % of patients during clinical trials in patients with NHL and in 30-50 % of patients during clinical trial in patients with CLL.

The most frequent reported or observed serious adverse drug reactions were:

• Infusion-related reactions (including cytokine-release syndrome, tumour-lysis syndrome), see section 4.4.

• Infections, see section 4.4.

• Cardiovascular events, see section 4.4.

Other serious ADRs reported include hepatitis B reactivation and PML (see section 4.4.).

The frequencies of ADRs reported with MabThera alone or in combination with chemotherapy are summarised in the tables below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (

Table 1 ADRs reported in clinical trials or during postmarketing surveillance in patients with NHL and CLL disease treated with MabThera monotherapy/maintenance or in combination with chemotherapy

System Organ Class	Very Common	Common	Uncommon	Unknown
Infections and infestations	bacterial infections, viral infections, +bronchitis	sepsis, +pneumonia, +febrile infection, +herpes zoster, +respiratory tract infection, fungal infections, infections of unknown aetiology, +acute bronchitis, +sinusitis, hepatitis B1		serious viral infection2,
Blood and lymphatic system disorders	neutropenia, leucopenia, +febrile neutropenia, + thrombocytopenia	anaemia, +pancytopenia, +granulocytopenia	coagulation disorders, aplastic anaemia, haemolytic anaemia, lymphadenopathy	late neutropenia3, transient increase in serum IgM levels3
Immune system disorders	infusion related reactions, angioedema	hypersensitivity		tumour lysis syndrome4, cytokine release syndrome4, serum sickness, anaphylaxis, infusion-related acute reversible thrombocytopenia4
Metabolism and nutrition disorders		hyperglycaemia, weight decrease, peripheral oedema, face oedema, increased LDH, hypocalcaemia
Psychiatric disorders			depression, nervousness,
Nervous system disorders		paraesthesia, hypoaesthesia, agitation, insomnia, vasodilatation, dizziness, anxiety	dysgeusia	cranial neuropathy, peripheral neuropathy facial nerve palsy5, loss of other senses5
Eye disorders		lacrimation disorder, conjunctivitis		severe vision loss5
Ear and labyrinth disorders		tinnitus, ear pain		hearing loss5
Cardiac disorders		+myocardial infarction4 and 6, arrhythmia, +atrial fibrillation, tachycardia, +cardiac disorder	+left ventricular failure, +supraventricular tachycardia, +ventricular tachycardia, +angina, +myocardial ischaemia, bradycardia,	heart failure4 and 6, severe cardiac events 4 and 6
Vascular disorders		hypertension, orthostatic hypotension, hypotension		vasculitis (predominately cutaneous), leukocytoclastic vasculitis
Respiratory, thoracic and mediastinal disorders		Bronchospasm4, respiratory disease, chest pain, dyspnoea, increased cough, rhinitis	asthma, bronchiolitis obliterans, lung disorder, hypoxia	respiratory failure4, pulmonary infiltrates, interstitial lung disease7
Gastrointestinal disorders	nausea	vomiting , diarrhoea, abdominal pain, dysphagia, stomatitis, constipation, dyspepsia, anorexia, throat irritation	abdominal enlargement	gastro-intestinal perforation7
Skin and subcutaneous tissue disorders	pruritis, rash, +alopecia	urticaria, sweating, night sweats, +skin disorder		severe bullous skin reactions, toxic epidermal necrolysis7
Musculoskeletal, connective tissue and bone disorders		hypertonia, myalgia, arthralgia, back pain, neck pain, pain
Renal and urinary disorders				renal failure4
General disorders and administration site conditions	fever, chills, asthenia, headache	tumour pain, flushing, malaise, cold syndrome, +fatigue, +shivering, +multi-organ failure4	pain at the infusion site
Investigations	decreased IgG levels
For each term, the frequency count was based on reactions of all grades (from mild to severe), except for terms marked with "+" where the frequency count was based only on severe ( 1 includes reactivation and primary infections; frequency based on R-FC regimen in relapsed/refractory CLL 2 see also section infection below 3 see also section haematologic adverse reactions below 4 see also section infusion-related reactions below. Rarely fatal cases reported 5 signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of MabThera therapy 6 observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated with infusion-related reactions 7 includes fatal cases

The following terms have been reported as adverse events during clinical trials, however, were reported at a similar or lower incidence in the MabThera-arms compared to control arms: haematotoxicity, neutropenic infection, urinary tract infection, sensory disturbance, pyrexia.

Infusion-related reactions

Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50% of patients in clinical trials, and were predominantly seen during the first infusion, usually in the first one to two hours. These symptoms mainly comprised fever, chills and rigors. Other symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnoea, dyspepsia, asthenia and features of tumor lysis syndrome. Severe infusion-related reactions (such as bronchospasm, hypotension) occurred in up to 12% of the cases. Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiac conditions such as angina pectoris or congestive heart failure or severe cardiac events (heart failure, myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower or unknown frequencies. The incidence of infusion-related symptoms decreased substantially with subsequent infusions and is <1% of patients by the eighth cycle of MabThera(-containing) treatment.

Infections

MabThera induces B-cell depletion in about 70-80% of patients, but was associated with decreased serum immunoglobulins only in a minority of patients.

Localized candida infections as well as Herpes zoster was reported at a higher incidence in the MabThera-containing arm of randomized studies. Severe infections were reported in about 4% of patients treated with MabThera monotherapy. Higher frequencies of infections overall, including grade 3 or 4 infections, were observed during MabThera maintenance treatment up to 2 years when compared to observation.There was no cumulative toxicity in terms of infections reported over a 2-year treatment period. In addition, other serious viral infections either new, reactivated or exacerbated, some of which were fatal, have been reported with MabThera treatment. The majority of patients had received MabThera in combination with chemotherapy or as part of a hematopoetic stem cell transplant. Examples of these serious viral infections are infections caused by the herpes viruses (Cytomegalovirus, Varicella Zoster Virus and Herpes Simplex Virus), JC virus (progressive multifocal leukoencephalopathy (PML)) and hepatitis C virus. Cases of fatal PML that occurred after disease progression and retreatment have also been reported in clinical trials. Cases of hepatitis B reactivation, have been reported, the majority of which were in subjects receiving MabThera in combination with cytotoxic chemotherapy. In patients with relapsed/refractory CLL, the incidence of grade 3/4 hepatitis B infection (reactivation and primary infection) was 2% in R-FC vs 0% FC. Progression of Kaposi's sarcoma has been observed in rituximab-exposed patients with pre-existing Kaposi's sarcoma. These cases occurred in non-approved indications and the majority of patients were HIV positive.

Haematologic adverse reactions

In clinical trials with MabThera monotherapy given for 4 weeks, haematological abnormalities occurred in a minority of patients and were usually mild and reversible. Severe (grade 3/4) neutropenia was reported in 4.2%, anaemia in 1.1% and thrombocytopenia in 1.7 % of the patients. During MabThera maintenance treatment for up to 2 years, leucopenia (5% vs. 2%, grade 3/4) and neutropenia (10% vs. 4 %, grade 3/4) were reported at a higher incidence when compared to observation. The incidence of thrombocytopenia was low ( <1 , grade 3/4%) and was not different between treatment arms. In studies with MabThera in combination with chemotherapy, grade 3/4 leucopenia (R-CHOP 88% vs. CHOP 79%, R-FC 23% vs. FC 12%), neutropenia (R-CVP 24% vs. CVP 14%; R-CHOP 97% vs. CHOP 88%, R-FC 30% vs. FC 19% in previously untreated CLL), pancytopenia (R-FC 3% vs. FC 1% in previously untreated CLL) were usually reported with higher frequencies when compared to chemotherapy alone. However, the higher incidence of neutropenia in patients treated with MabThera and chemotherapy was not associated with a higher

Permax

Generic Name: pergolide (Oral route)

PER-goe-lide

Oral route(Tablet)

The use of pergolide has been shown to increase the risk of cardiac valvular disease and is not recommended for use in patients with a history of cardiac valvulopathy. Some patients have required valve replacement, and deaths have been reported. Periodic echocardiograms are recommended during therapy. Pergolide increases the risk of fibrotic complications including pulmonary, pleural, and/or retroperitoneal fibrosis, pericarditis, pleuritis, and pericardial and/or pleural effusions. Pergolide is not recommended for use in patients with a history of fibrotic conditions and patients should be monitored for fibrotic complications during therapy .

Commonly used brand name(s)

In the U.S.

• Permax

Available Dosage Forms:

• Tablet

Therapeutic Class: Antiparkinsonian

Pharmacologic Class: Dopamine Agonist

Uses For Permax

Pergolide belongs to the group of medicines known as ergot alkaloids. It is used with levodopa or with carbidopa and levodopa combination to treat people who have Parkinson's disease. It works by stimulating certain parts of the central nervous system (CNS) that are involved in this disease.

Pergolide was available only with your doctor's prescription.

This medicine was withdrawn from the U.S. market in March 2007 due to an increased risk for heart valve problems .

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although this use is not included in the product labeling, pergolide is used in certain patients with the following medical condition:

• Restless legs syndrome

Before Using Permax

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Studies on this medicine have been done only in adult patients, and there is no specific information about its use in children.

Geriatric

This medicine has been tested and has not been shown to cause different side effects or problems in older people than it does in younger adults.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

Studies suggest that this medication may alter milk production or composition. If an alternative to this medication is not prescribed, you should monitor the infant for side effects and adequate milk intake.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Frovatriptan

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Kava

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Heart disease or


• Mental problems (history of)—Pergolide may make the condition worse.

Proper Use of Permax

If pergolide upsets your stomach, it may be taken with meals. If stomach upset continues, check with your doctor.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  
  • Adults—50 micrograms a day for the first two days. The dose may be increased every three days as needed. However, the usual dose is not more than 5000 micrograms.
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Permax

It is important that your doctor check your progress at regular visits, to make sure that this medicine is working and to check for unwanted effects.

This medicine may cause some people to become drowsy, dizzy, or less alert than they are normally. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or are not alert.

Dizziness, lightheadedness, or fainting may occur after the first doses of pergolide, especially when you get up from a lying or sitting position. Getting up slowly may help. Taking the first dose at bedtime or when you are able to lie down may also lessen problems. If the problem continues or gets worse, check with your doctor.

Pergolide may cause dryness of the mouth. For temporary relief, use sugarless candy or gum, melt bits of ice in your mouth, or use a saliva substitute. However, if your mouth continues to feel dry for more than 2 weeks, check with your medical doctor or dentist. Continuing dryness of the mouth may increase the chance of dental disease, including tooth decay, gum disease, and fungus infections.

It may take several weeks for pergolide to work. Do not stop taking this medicine or reduce the amount you are taking without first checking with your doctor.

Permax Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

Rare

• Chest pain (severe)


• convulsions (seizures)


• difficulty in breathing


• fainting


• fast heartbeat or irregular pulse


• headache (severe or continuing)


• high fever


• high or low (irregular) blood pressure


• increased sweating


• loss of bladder control


• nausea and vomiting (continuing or severe)


• nervousness


• severe muscle stiffness


• sudden weakness


• unexplained shortness of breath


• unusual tiredness or weakness


• unusually pale skin


• vision changes, such as blurred vision or temporary blindness

Check with your doctor as soon as possible if any of the following side effects occur:

More common

• Anxiety


• bloody or cloudy urine


• confusion


• difficult or painful urination


• frequent urge to urinate


• hallucinations (seeing, hearing, or feeling things that are not there)


• uncontrolled movements of the body, such as the face, tongue, arms, hands, head, and upper body

Less common

• Dizziness


• headache


• swelling in hands and legs

Rare

• Abdominal pain or pressure


• chills


• cough


• decreased flow of urine


• fever


• pain in side or lower back

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Chest congestion


• constipation


• dizziness or lightheadedness, especially when getting up from a lying or sitting position


• drowsiness


• heartburn


• lower back pain


• muscle pain


• nausea


• runny or stuffy nose


• trouble in sleeping


• weakness

Less common

• Diarrhea


• dryness of mouth


• loss of appetite


• swelling of the face


• vomiting

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Permax side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Permax resources

• Permax Side Effects (in more detail)
• Permax Dosage
• Permax Use in Pregnancy & Breastfeeding
• Drug Images
• Permax Drug Interactions
• Permax Support Group
• 0 Reviews for Permax - Add your own review/rating

• Permax Prescribing Information (FDA)


• Permax MedFacts Consumer Leaflet (Wolters Kluwer)


• Permax Concise Consumer Information (Cerner Multum)


• Permax Monograph (AHFS DI)


• Pergolide Prescribing Information (FDA)

Compare Permax with other medications

• Hyperprolactinemia
• Parkinson's Disease
• Tourette's Syndrome

Nebivolol 5mg Tablets

Nebivolol 5mg tablets

(nebivolol hydrochloride)

Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as
  yours.


• 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.

In this leaflet:

• 
  1 What Nebivolol 5mg tablets are and what they are used for
  


• 
  2 Before you take
  


• 
  3 How to take
  


• 
  4 Possible side effects
  


• 
  5 How to store
  


• 
  6 Further information
  

What Nebivolol 5mg tablets are and what they are used for

Nebivolol 5mg tablets belong to a group of medicines known as beta-blockers. They work by blocking the activity of specific proteins in the heart, lungs, pancreas, liver, and blood circulation system.

Nebivolol 5mg tablets are used to treat.

• high blood pressure (hypertension)


• chronic heart failure in patients aged 70 years or older.

Before you take

Do not take Nebivolol 5mg tablets if you:

• are allergic (hypersensitive) to nebivolol or any of the other ingredients of Nebivolol 5mg tablets.


• suffer from liver problems.


• have low blood pressure or poor circulation in the arms or legs.


• have a very slow heart beat (less than 60 beats per minute)


• have certain serious heart rhythm problems.


• have the condition heart failure which has just occurred or which has recently become worse.


• have asthma or wheezing (now or in the past).


• have been told by your doctor that you have a tumour in your adrenal gland which is located on top of the kidneys (the medical term for this is an untreated phaeochromocytoma).


• have metabolic acidosis such as diabetic ketoacidosis.

If you are unsure, contact your doctor.

Take special care with Nebivolol 5mg tablets:

Tell your doctor before you start to take this medicine if you:

• notice that your heart rate is abnormally slow or you experience shortness of breath or dizziness.


• have ischaemic heart disease such as angina (chest pains).


• have been told you suffer from any of the following conditions:
  
  
  • Poor blood circulation which makes the toes and fingers numb and pale (Raynaud’s disease)
  • A type of chest pain due to spontaneously occurring heart cramp called Prinzmetal angina.
  • Pain, tension and weakness in the legs when walking which is relieved by rest (Intermittent claudication).
  • A persistent obstruction of your airway such as chronic bronchitis.
  • Diabetes, as it can hide the warning signs of low sugar levels.
  • Over activity of the thyroid gland (Hyperthyroidism).
  • A skin condition known as psoriasis.
  • Impairment of the electrical conduction of signals in the heart (First degree heart block).


• are being treated with any other drugs which lower your blood pressure.

If you need to have an operation and need an anaesthetic, it is important that you tell the surgeon or dentist that you are taking this medicine.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

The following medicines may interact with nebivolol by decreasing or increasing its effects:

• Calcium channel blockers, used to treat high blood pressure or other heart problems, such as verapamil, diltiazem, amlodipine,
  felodipine, lacidipine, nifedipine, nicardipine, nimodipine and nitrendipine. It is particularly important that verapamil is not injected into a vein during treatment with nebivolol.


• Clonidine, guanfacine, moxonidine, methyldopa and rilmenidine, which are used to treat high blood pressure.


• Quinidine, hydroquinidine, amiodarone, cibenzoline, flecainide, disopyramide, lidocaine, mexiletine and propafenone, which are used to treat cardiac arrhythmias (irregular heartbeat).


• Barbiturates and phenothiazine, which are used to treat anxiety.


• Amitriptyline, trazodone, paroxetine, fluoxetine and thioridiazine, which are used to treat depression.


• Asthma medications, medications for blocked nose (e.g. pseudoephedrine) or for certain eye disorders such as glaucoma (increased pressure in the eye) or dilation of the pupil.


• Medicines for diabetes (insulin and medicines for oral use).


• Anaesthetics. Always inform your anaesthetist that you are on nebivolol before being anaesthetized.


• Antacids (e.g. cimetidine), which are used to treat excessive stomach acid. If you are being treated for excessive stomach acid,
  you should take nebivolol during a meal, and the antacid drug between meals.


• Dextromethorphan (found in cough medicines).


• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as ibuprofen and diclofenac, which are used to treat certain types of pain and inflammation.

Taking Nebivolol 5mg tablets with food and drink

Nebivolol can be taken with or without food unless you take antacids (see “Taking other medicines”). The tablet should be swallowed with a glass of water or other liquid.

Pregnancy and breast-feeding

Nebivolol should not be used during pregnancy, unless clearly necessary. It is not recommended for use while breast-feeding.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Nebivolol may cause tiredness and/or dizziness and if you are affected you should not drive or use any machines or tools.

Sugar intolerance

This medicine contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your
doctor before taking this medicine.

How to take

Always take Nebivolol 5mg tablets exactly as your doctor has told you. You should check with your doctor or pharmacist if you are
not sure.

Treatment of high blood pressure (hypertension)

The usual dose is one tablet (5mg) daily, although elderly patients and patients with kidney problems may begin treatment on a lower dose.

The blood pressure lowering effect may take up to 1-2 weeks of treatment to become evident. Occasionally, the optimal effect is only reached after 4 weeks.

Treatment of chronic heart failure

The usual initial dose is 1.25mg daily. This may be increased after 1-2 weeks to half a tablet daily (2.5mg) and then to 1 tablet daily
(5mg). This may be further increased to a maximum recommended dose of 2 tablets daily (10mg).

Your doctor may reduce your dose if necessary. Every time your dose is changed, your doctor will monitor you for approximately two hours.

Your doctor may decide to combine your tablets with other medicines for your condition.

Children and Adolescents

There are limited data in children and hence Nebivolol 5 mg tablets are not recommended in children and adolescents under 18 years of age.

If you take more Nebivolol 5mg tablets than you should

If you accidentally take too much nebivolol, tell your doctor immediately or go to your nearest accident and emergency department.

If you forget to take Nebivolol 5mg tablets

If you forget to take a dose, take one as soon as you remember, unless it is almost time for your next dose. Then go on as before. Do not take a double dose to make up for a forgotten dose.

If you stop taking Nebivolol 5mg tablets

You should not stop treatment abruptly as this can worsen heart failure. Your doctor will reduce your dose of nebivolol gradually.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Possible Side Effects

Like all medicines, Nebivolol 5mg tablets can cause side effects, although not everybody gets them.

Hypertension

The side effects reported in people taking nebivolol for hypertension are listed below:

The following side effects have been reported only in some isolated cases during Nebivolol treatment

• whole-body allergic reaction, with generalised skin eruption (hypersensitivity reactions)

Very rare Side Effects (that affect fewer than 1 person in every 10,000 treated)

• fainting


• worsening of psoriasis (a skin disease - scaly pink patches)


• rapid-onset swelling, especially around the lips, eyes, or of the tongue with sudden difficulty breathing (angioedema).

Uncommon Side Effects (that affect more than 1 person in every 1000 but fewer than 1 person in 100)

• Slow heartbeat or other heart complaints


• Low blood pressure


• Cramp-like leg pains on walking


• Abnormal vision


• Impotence


• Depressive feelings


• Indigestion


• Gas in stomach or bowel


• Vomiting


• Skin rash


• Tightness in the throat


• Nightmares


• Itching

Common Side Effects (that affect more than 1 person in every 100 treated but fewer than 1 person in every 10 treated)

• Headache


• Dizziness


• Tiredness


• An unusual itching or tingling feeling


• Diarrhoea


• Constipation


• Nausea (feeling sick)


• Shortness of breath


• Swollen hands or feet

Chronic Heart Failure

The side effects reported in people taking nebivolol for chronic heart failure are listed below:

Common Side Effects (that affect more than 1 person in every 100 treated but fewer than 1 person in every 10 treated)

• Worsening of heart failure


• Low blood pressure (with symptoms such as feeling faint when you get up quickly)


• Inability to tolerate the medicine


• Irregular heartbeat


• Swollen legs, ankles, or feet

Very Common Side Effects (that affect more than 1 person in every 10 treated)

• Slow heartbeat


• Dizziness

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.

How to store

Keep out of the reach and sight of children.

This medicinal product does not require any special storage conditions.

Do not use Nebivolol 5mg tablets after the expiry date which is stated on the carton after Exp.. The expiry date refers to the last day of that month.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further information

What Nebivolol 5mg tablets contain

The active substance is nebivolol hydrochloride corresponding to 5mg nebivolol.

The other ingredients are silica colloidal anhydrous, magnesium stearate, croscarmellose sodium, macrogol 6000, and lactose monohydrate.

What Nebivolol 5mg tablets look like and contents of the pack

Round, white, biconvex tablets with a cross-score on one side and marked “N5” on the other. The tablets can be divided into equal quarters.

Pack size: 28 tablets

Marketing Authorisation Holder

Actavis Group PTC ehf

Reykjavikurvegi 76-78

220 Hafnarfjordur

Iceland

Manufacturer

Actavis Ltd

BLB016 Bulebel Industrial Estate

Zejtun ZTN 3000

Malta

This leaflet was last revised July 2009

Actavis

Barnstaple

EX32 8NS

UK

ACTPL082

Maxair

Generic Name: pirbuterol inhaler (peer BYOO ter ole)

Brand Names: Maxair, Maxair Autohaler

What is pirbuterol inhalation?

Pirbuterol is a bronchodilator. It works by relaxing muscles in the airways to improve breathing.

Pirbuterol inhalation is used to treat conditions such as asthma, bronchitis, and emphysema.

Pirbuterol inhalation may also be used for conditions other than those listed in this medication guide.

What is the most important information I should know about pirbuterol inhalation?

It is very important that you use your pirbuterol inhaler properly, so that the medicine gets into your lungs. Your doctor may want you to use a spacer with your inhaler. Talk to your doctor about proper inhaler use.

Seek medical attention if you notice that you require more than your usual or more than the maximum amount of any asthma medication in a 24-hour period. An increased need for medication could be an early sign of a serious asthma attack.

Who should not use pirbuterol inhalation?

Before using this medication, tell your doctor if you have

• 
  

  heart disease or high blood pressure,

  
  


• 
  

  epilepsy or another seizure disorder,

  
  


• 
  

  diabetes,

  
  


• 
  

  an overactive thyroid (hyperthyroidism), or

  
  


• 
  

  any type of liver or kidney disease.

  
  

You may require a lower dose or special monitoring during therapy with pirbuterol if you have any of the conditions listed above.

Pirbuterol is in the FDA pregnancy category C. This means that it is not known whether pirbuterol inhalation will harm an unborn baby. Do not use this medication without first talking to your doctor if you are pregnant. It is not known whether pirbuterol passes into breast milk. Do not use pirbuterol inhalation without first talking to your doctor if you are breast-feeding a baby. Pirbuterol inhalation is not approved for use by children younger than 12 years of age.

How should I use pirbuterol inhalation?

Take pirbuterol inhalation exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse or doctor to explain them to you.

Shake the inhaler several times and uncap the mouthpiece. Breathe out fully and place your lips around the mouthpiece. Take a deep, slow breath as you push down on the canister. Hold your breath for several seconds, then exhale slowly.

The Autohaler releases the correct amount of drug. The force of your inhalation will trigger the release. You do not have to press down on a canister. Follow the instructions that accompany your inhaler.

If you take more than one dose at a time, wait for at least 1 full minute, then repeat the procedure.

Rinse your mouth after each use of the inhaler.

If you also use a steroid inhaler, use your pirbuterol inhaler first to open up your airways, then use the steroid inhaler as directed.

It is very important that you use your pirbuterol inhaler properly, so that the medicine gets into your lungs. Your doctor may want you to use a spacer with your inhaler. Talk to your doctor about proper inhaler use.

Seek medical attention if you notice that you require more than your usual or more than the maximum amount of any asthma medication in a 24-hour period. An increased need for medication could be an early sign of a serious asthma attack.

Keep your inhaler clean and dry. Keep the mouthpiece capped to avoid getting dirt inside it. Clean your inhaler once a day by removing the canister and mouthpiece and immersing it in warm water or alcohol. Allow the parts to dry, then reassemble the inhaler.

Carry your inhaler with you at all times in case of emergencies. Get a refill before you run out of medicine and before going on vacation.

What happens if I miss a dose?

Use the missed dose as soon as you remember. However, if it is almost time for your next regularly scheduled dose, skip the missed dose and use the next one as directed. Do not use a double dose of this medication.

What happens if I overdose?

Seek emergency medical attention.

Symptoms of a pirbuterol overdose include angina or chest pain, irregular heartbeats or a fluttering heart, seizures, tremor, weakness, headache, nausea, and vomiting.

What should I avoid while using pirbuterol inhalation?

Avoid situations that may trigger an asthma attack such as exercising in cold, dry air; smoking; breathing in dust; and exposure to allergens such as pet fur.

Pirbuterol inhalation side effects

Stop using pirbuterol and seek emergency medical attention if you experience any of the following serious side effects:

• 
  

  an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives); or

  
  


• 
  

  chest pain or irregular heartbeats.

  
  

Other, less serious side effects may be more likely to occur. Continue to use pirbuterol inhalation and talk to your doctor if you experience

• 
  

  headache, dizziness, lightheadedness, or insomnia;

  
  


• 
  

  tremor or nervousness;

  
  


• 
  

  sweating;

  
  


• 
  

  nausea, vomiting, or diarrhea; or

  
  


• 
  

  dry mouth.

  
  

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect pirbuterol?

Before using this medication, tell your doctor if you are taking any of the following medicines:

• a beta-blocker (used to treat high blood pressure and other heart conditions) such as atenolol (Tenormin), metoprolol (Lopressor), or propranolol (Inderal). These medicines may greatly decrease the effects of pirbuterol and lead to an asthma attack.


• other commonly used beta-blockers, including acebutolol (Sectral), bisoprolol (Zebeta), carteolol (Cartrol), carvedilol (Coreg), labetalol (Normodyne, Trandate), nadolol (Corgard), and pindolol (Visken).


• a tricyclic antidepressant such as amitriptyline (Elavil), doxepin (Sinequan), or nortriptyline (Pamelor). Very high blood pressure and other effects harmful to the heart may occur if these medicines are taken with pirbuterol.


• other commonly used tricyclic antidepressants, including amoxapine (Asendin), clomipramine (Anafranil), desipramine (Norpramin), imipramine (Tofranil), and protriptyline (Vivactil).


• a monoamine oxidase (MAO) inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate). Very high blood pressure and other effects harmful to the heart may also occur if these medicines are taken with pirbuterol.


• 
  

  another inhaled bronchodilator such as albuterol (Ventolin, Proventil), bitolterol (Tornalate), isoetharine (Bronkometer, Bronkosol), isoproterenol (Isuprel, Medihaler-Iso), metaproterenol (Alupent, Metaprel), salmeterol (Servent), or terbutaline (Brethaire, Brethine, Bricanyl). Using other inhaled medicines to open up your lungs will increase the risk of damage to your heart when you are taking pirbuterol.

  
  


• 
  

  caffeine, diet pills, or decongestants. These may also increase heart-related side effects.

  
  

Drugs other than those listed here may also interact with pirbuterol inhalation, or affect your condition. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines.

More Maxair resources

• Maxair Side Effects (in more detail)
• Maxair Use in Pregnancy & Breastfeeding
• Maxair Drug Interactions
• Maxair Support Group
• 1 Review for Maxair - Add your own review/rating

• Maxair Prescribing Information (FDA)


• Maxair Advanced Consumer (Micromedex) - Includes Dosage Information


• Maxair Autohaler Prescribing Information (FDA)


• Maxair Autohaler MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Maxair with other medications

• Asthma, acute
• Asthma, Maintenance
• COPD, Acute
• COPD, Maintenance

Where can I get more information?

• Your pharmacist has additional information about pirbuterol written for health professionals that you may read.

See also: Maxair side effects (in more detail)

Tobramycin/Dexamethasone Drops

Pronunciation: TOE-bra-MYE-sin/DEX-a-METH-a-sone
Generic Name: Tobramycin/Dexamethasone
Brand Name: TobraDex ST

Tobramycin/Dexamethasone Drops are used for:

Treating certain types of eye inflammation where a bacterial infection exists or may develop.

Tobramycin/Dexamethasone Drops are an antibiotic (tobramycin) and a corticosteroid (dexamethasone) combination. The antibiotic works by preventing the growth of, or killing, sensitive bacteria in the eye. The corticosteroid works by reducing inflammatory reactions.

Do NOT use Tobramycin/Dexamethasone Drops if:

• you are allergic to any ingredient in Tobramycin/Dexamethasone Drops


• you have a mycobacterial, fungal, or viral (eg, herpes simplex, vaccinia, chickenpox) eye infection

Contact your doctor or health care provider right away if any of these apply to you.

Before using Tobramycin/Dexamethasone Drops:

Some medical conditions may interact with Tobramycin/Dexamethasone Drops. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, plan to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, especially to other aminoglycosides (eg, gentamicin); foods; or other substances


• if you have thinning of the cornea (the surface of the eye), or oozing from the eye


• if you have diabetes, glaucoma or increased eye pressure, or have recently had cataract surgery


• if you have a history of viral eye infections (eg, herpes simplex)


• if you are using another form of aminoglycoside antibiotic (eg, intravenous)

Some MEDICINES MAY INTERACT with Tobramycin/Dexamethasone Drops. Because little, if any, of Tobramycin/Dexamethasone Drops are absorbed into the blood, the risk of interacting with another medicine is low.

Ask your health care provider if Tobramycin/Dexamethasone Drops may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Tobramycin/Dexamethasone Drops:

Use Tobramycin/Dexamethasone Drops as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Tobramycin/Dexamethasone Drops are only for the eye. Do not get it in your nose or mouth. Do not inject it into the eye.


• Shake well before each use.


• To use Tobramycin/Dexamethasone Drops in the eye, first wash your hands. Tilt your head back. Using your index finger, pull the lower eyelid away from the eye to form a pouch. Drop the medicine into the pouch and gently close your eyes. Immediately use your finger to apply pressure to the inside corner of the eyelid for 1 to 2 minutes. Do not blink. Remove excess medicine around your eye with a clean, dry tissue, being careful not to touch your eye. Wash your hands to remove any medicine that may be on them.


• To prevent germs from contaminating your medicine, do not touch the applicator tip to any surface, including the eye. Keep the container tightly closed.


• Do not wear contact lenses while you are using Tobramycin/Dexamethasone Drops. Take care of your contact lenses as directed by the manufacturer. Check with your doctor before you use them.


• Using Tobramycin/Dexamethasone Drops at the same time each day will help you to remember to use it.


• To clear up your infection completely, use Tobramycin/Dexamethasone Drops for the full course of treatment. Keep using it even if you feel better in a few days.


• If you miss a dose of Tobramycin/Dexamethasone Drops, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Tobramycin/Dexamethasone Drops.

Important safety information:

• Tobramycin/Dexamethasone Drops may cause blurred vision. Use Tobramycin/Dexamethasone Drops with caution. Do not drive or perform other possibly unsafe tasks if you cannot see clearly.


• If your symptoms do not improve within 2 days or if they get worse, check with your doctor.


• Check with your doctor if you have an eye wound or irritation that does not heal.


• Prolonged use of Tobramycin/Dexamethasone Drops (eg, 10 days or longer) may increase the risk of glaucoma. Your doctor may monitor the pressure in your eye(s) while you use Tobramycin/Dexamethasone Drops. Discuss any questions or concerns with your doctor.


• Be sure to use Tobramycin/Dexamethasone Drops for the full course of treatment. If you do not, the medicine may not clear up your infection completely. The bacteria could also become less sensitive to this or other medicines. This could make the infection harder to treat in the future.


• Long-term or repeated use of Tobramycin/Dexamethasone Drops may cause a second infection. Tell your doctor if signs of a second infection occur. Your medicine may need to be changed to treat this.


• Do not use Tobramycin/Dexamethasone Drops for future eye problems unless directed by your doctor.


• Tobramycin/Dexamethasone Drops should be used with extreme caution in CHILDREN younger than 2 years old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Tobramycin/Dexamethasone Drops while you are pregnant. It is not known if Tobramycin/Dexamethasone Drops are found in breast milk after topical use. If you are or will be breast-feeding while you use Tobramycin/Dexamethasone Drops, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Tobramycin/Dexamethasone Drops:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Burning or stinging when you first put the medicine in your eye.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); changes in vision; itching or swelling of the eyelid; new or worsening eye pain, redness, swelling, or irritation; vision loss.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include increased tearing; lid itching; redness or swelling of the eye.

Proper storage of Tobramycin/Dexamethasone Drops:

Store Tobramycin/Dexamethasone Drops between 36 and 77 degrees F (2 and 25 degrees C). Store upright in the original container, tightly closed, and away from heat, moisture, and light. Do not store in the bathroom. Keep Tobramycin/Dexamethasone Drops out of the reach of children and away from pets.

General information:

• If you have any questions about Tobramycin/Dexamethasone Drops, please talk with your doctor, pharmacist, or other health care provider.


• Tobramycin/Dexamethasone Drops are to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Tobramycin/Dexamethasone Drops. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Tobramycin/Dexamethasone resources

• Tobramycin/Dexamethasone Use in Pregnancy & Breastfeeding
• Tobramycin/Dexamethasone Drug Interactions
• Tobramycin/Dexamethasone Support Group
• 3 Reviews for Tobramycin/Dexamethasone - Add your own review/rating

Compare Tobramycin/Dexamethasone with other medications

• Conjunctivitis, Bacterial
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