Common side effects (occurring in at least 1 in 100 patients) that may occur during treatment with Suboxone are: weight loss, swelling (hands and feet), tiredness, drowsiness, anxiety, nervousness, tingling, depression, decreased sexual drive, muscle spasms, abnormal thinking, tearing disorder, blurred vision, flushing, increased blood pressure, migraines, runny nose, sore throat and painful swallowing, increased cough, upset stomach, diarrhoea, abnormal liver function, loss of appetite, flatulence, vomiting, rash, itching, hives, pain, joint pain, muscle pain, leg cramps, impotence, urine abnormality, abdominal pain, back pain, weakness, infection, chills, chest pain, fever, flu syndrome, feeling of general discomfort, accidental injury, faintness and dizziness, drop in blood pressure on changing position from sitting or lying down to standing.

Additional adverse reactions were observed in patients treated with the aprepitant (125 mg/ 80 mg) regimen for chemotherapy induced nausea and vomiting and at a greater incidence than with standard therapy: abdominal pain, acid reflux, acne, alkaline phosphatase increased, anaemia, anorexia, anxiety, AST increased, asthaenia/ fatigue, candidiasis, chest discomfort, cognitive disorder, conjunctivitis, constipation, cough, diarrhoea, disorientation, dizziness, dream abnormality, dysgeusia, dyspepsia, dysuria, enterocolitis, epigastric discomfort, eructation, euphoria, febrile neutropenia, flatulence, flushing, gastroesophageal reflux disease, headache, hiccups, hot flush, hyperglycaemia, hyperhidrosis, hyponatraemia, lethargy, microscopic haematuria, muscle cramp, myalgia, nausea*, obstipation, oedema, oily skin, perforating duodenal ulcer, pharyngitis, photosensitivity, pollakiuria,

• Loss of appetite • Change in perception of self, restlessness, depression, agitation, mood swings, insomnia worsened, difficulty finding words, hallucinations, abnormal dreams, panic attacks, apathy • Difficulty with thinking, numbness, unusual eye movement, jerky movements, reduced reflexes, increased activity, dizziness on standing, sensitive skin, loss of taste, burning sensation, tremor on movement, decreased consciousness, fainting • Dry eyes, eye swelling, eye pain, weak eyes, watery eyes • Increased heart rate • Flushing, hot flushes • Difficulty breathing, dry nose • Swollen abdomen, increased saliva production, heartburn, numb around mouth • Sweating, rash • Muscle twitching, joint swelling, muscle cramp, muscle pain, joint pain, back pain, pain in limb, muscle stiffness • Difficulty with or painful urination, incontinence, • Weakness, fall, thirst, chest tightness

Uncommon (occurring in greater than 1 out of 1000 and less than 1 out of 100 people) Stomach or bowel bloating, chest pain, heart failure, heart attack, stroke, mini-stroke (transient ischaemic attack), abnormal heart rhythm (atrial fibrillation), upper respiratory infection, high levels of potassium in your blood, changes in blood or urine tests relating to your kidney, changes in your bowel habits including constipation, dry mouth, mouth ulcers, taste alteration, gastroenteritis, gastritis, stomach ulcer, being sick (vomiting), irritable bowel syndrome, inflammation of the esophagus, blurred vision, eye irritation and redness, nose bleed, ringing in the ears, vertigo, appetite increases or decreases, weight gain, muscle cramp/ spasm, muscle pain/ stiffness, inability to sleep, sleepiness, numbness or tingling, anxiety, depression, 37 decreases in mental sharpness, breathlessness, cough, swelling of the face, flushing, skin rash or itchy skin, urinary tract infection.

Uncommon (occurring in greater than 1 out of 1000 and less than 1 out of 100 people) Stomach or bowel bloating, chest pain, heart failure, heart attack, stroke, mini-stroke (transient ischaemic attack), abnormal heart rhythm (atrial fibrillation), upper respiratory infection, high levels of potassium in your blood, changes in blood or urine tests relating to your kidney, changes in your bowel habits including constipation, dry mouth, mouth ulcers, taste alteration, gastroenteritis, gastritis, stomach ulcer, being sick (vomiting), irritable bowel syndrome, inflammation of the esophagus, blurred vision, eye irritation and redness, nose bleed, ringing in the ears, vertigo, appetite increases or decreases, weight gain, muscle cramp/ spasm, muscle pain/ stiffness, inability to sleep, sleepiness, numbness or tingling, anxiety, depression, 40 decreases in mental sharpness, breathlessness, cough, swelling of the face, flushing, skin rash or itchy skin, urinary tract infection.

Uncommon side effects include (occurs in less than 1 patient of 100): thrombocytopenia (low platelets, which may result in easy bleeding), leukopenia (low white blood cells), gout, nervousness, tremor (trembling), blurred vision, tinnitus (ringing or noise in the ears), vertigo (a feeling of dizziness or ‘ spinning’), arrythmia (a feeling of irregular heart beat), tachycardia (increased heart rate), palpitations, angina pectoris, myocardial infarction (heart attack), cerebrovascular accident (stroke), dyspnoea (shortage of breath), cough, bronchial spasms, epistaxis (nosebleed), anorexia (loss of appetite), obstipation (constipation), increased appetite, icterus (jaundice), liver enzyme increases, rash, pruritus (itching), purpura (rash caused by bleeding under the skin), myalgia (painful muscles), arthralgia (painful joints), muscle cramps, increased diuresis (increased volume of urine passed), haematuria (blood in the urine), urinary incontinence, priapism (painful persistent erection), impotence, chest pain, agitation, facial flushing.

Uncommon (affects less than 1 in 100 people) • Skin rash with or without raised area • Flushing, fainting, hypotension (abnormally low blood pressure), especially when you stand or sit up quickly • Balance problems (vertigo) • Itching and unusual skin sensations such as numbness, tingling, pricking, burning or creeping on your skin (paraesthesia) • Loss or change in the way things taste • Sleep problems • Feeling depressed, anxious, more nervous or shaky than usual • Blocked nose, inflammation of your sinuses (sinusitis), shortness of breath • Inflammation of the gums (gingivitis), swollen mouth • Red, itchy, swollen or watery eyes • Ringing in your ears • Blurred vision • Hair loss • Chest pain • Pain in your muscles • Constipation, stomach or gut pain • Indigestion or feeling sick • Passing more water (urine) than usual over the day • Sweating more than usual or feeling thirsty • Loss or decrease of appetite (anorexia), feeling less hungry • Increased or irregular heartbeat • Swollen arms and legs.

Commonly reported side effects (at least 1 in every 100 patients, but less than 1 in every 10 patients): thirst, dehydration, high blood pressure, migraines, swollen glands, flushing, menstrual problems, decreased sexual drive, vaginal problem, breast pain, pain in testicle, problems with thyroid gland, red gums, dry mouth, red or sore mouth or tongue, tooth ache or tooth disorder, herpes simplex (fever blisters), taste change, upset stomach, dyspepsia (heartburn), constipation, enlargement of liver (liver problems, sometimes severe), loose stools, bedwetting in children, inflammation of the sinuses, bronchitis, eye pain, problem with your tear ducts, conjunctivitis (“pink eye”), agitation, sleepiness, sleepwalking, problem with behaviour, nervousness, stuffy or runny nose, sneezing, rapid breathing, pale or reddened skin, bruising, fingers and toes very sensitive to cold, problem with skin or nails, psoriasis (new or worsened), increased sweating, increased need to pass urine, fine shaking movements, decreased sensitivity to touch, arthritis.

Common side effects Infections: pneumonia, herpes viral infection, upper respiratory infection, serious infection of the blood or tissues (including fatal outcome) Heart and lungs: palpitations, flushing, dizziness, congestive heart failure, cardiac dysfunction, high blood pressure Digestive problems: appetite disturbances, taste disturbance, bloated or distended tummy (abdomen), inflammation of the colon, constipation, heartburn, mouth ulceration, weight increase, weight decrease, gastritis Skin, hair, eye, general: skin tingling, itching, dry skin, acne, inflamation of the skin, persistant noise in ears, hair loss, excessive perspiration, visual disorder (including blurred vision and disturbed vision), dry eye, haematoma, depression, insomnia, contusion, anorexia, somnolence, generalised oedema Pain: pain in joints, muscle inflammation, muscular weakness, chest pain, pain around hands and feet, chills Tests may show: fluid around the heart, fluid in the lungs, arrhythmia, febrile neutropenia, deficiency in all blood cells, gastrointestinal bleeding

Commonly reported side effects (at least 1 in every 100 patients, but less than 1 in every 10 patients): thirst, dehydration, high blood pressure, migraines, swollen glands, flushing, menstrual problems, decreased sexual drive, vaginal problem, breast pain, pain in testicle, problems with thyroid gland, red gums, dry mouth, red or sore mouth or tongue, tooth ache or tooth disorder, herpes simplex (fever blisters), taste change, upset stomach, dyspepsia (heartburn), constipation, enlargement of  452 liver (liver problems, sometimes severe), loose stools, bedwetting in children, inflammation of the sinuses, bronchitis, eye pain, problem with your tear ducts, conjunctivitis (“pink eye”), agitation, sleepiness, sleepwalking, problem with behaviour, nervousness, stuffy or runny nose, sneezing, rapid breathing, pale or reddened skin, bruising, fingers and toes very sensitive to cold, problem with skin or nails, psoriasis (new or worsened), increased sweating, increased need to pass urine, fine shaking movements, decreased sensitivity to touch, arthritis.

85 • Tasting things differently than usual, disturbance in attention or spasms and involuntary movements of the muscles. • Weight loss or weight gain, burping, indigestion or gastroenteritis. • Inflammation of the liver that may cause abdominal pain, tiredness or yellow coloration of the skin. • Vertigo, tinnitus (perception of sound in the ear when there is no external sound, ear pain. • Larger pupils (the dark centre of the eye) or visual disturbance. • Flushing, increase in blood pressure, feeling cold in your fingers and/ or toes, feeling dizzy (particularly when standing up too quickly), fast or irregular heart beat, night sweats, cold sweats, shivering or fainting. • Changes in ejaculation, abnormal periods, including heavy or prolonged periods • Allergic reactions, increased tendency to bruise, blisters or sensitivity to sunlight. • Muscle twitching. • Need to pass urine during the night or difficulty or inability to pass urine. • Grinding of teeth, dehydration, feeling hot/ cold, thirst, throat tightness or nose bleeds • Increased level of cholesterol in the blood.

Other known side effects associated with fentanyl products include: • Very common side effects (affects more than 1 user in 10 people): excessive sweating • Common side effects (affects 1 to 10 users in 100): feeling confused, feeling anxious or nervous, hallucinations, abnormal thinking, muscle twitching, difficulty sleeping, strange dreams, tongue or taste problems, flushing, mouth ulcers/ blisters, blockage of the gut, difficulty swallowing, being accident-prone • Uncommon side effects (affects 1 to 10 users in 1,000): feeling restless, feeling detached, moodswings, trembling, difficulty speaking, being forgetful, loss of coordination, vertigo, slow or fast heartbeat, high blood pressure, difficulty breathing, slow or shallow breathing, asthma, bloating, wind, thirst, difficulty going to the toilet, change in frequency of going to the toilet, feeling unwell • Rare side effects (affects 1 to 10 users in 10,000): hiccups • Very rare side effects (affects less than 1 user in 10,000): irregular heartbeat, stopping breathing, blood in the saliva, decrease in amount of urine, painful contraction of the bladder

Less common are pain at the place of injection, flushing, low or high blood pressure, dry or teary eyes, redness of skin or skin disorders, psoriasis, hives, nail disorder, feeling unwell, feeling faint, poor coordination, confusion, increased or decreased sensitivity to touch, tense muscles, arthritis, bruising, loss of interest in activities including sex, sexual problem, unusual dreams, shaky hands, vertigo (spinning feeling), increased appetite, heartburn, intestinal gas (flatus), constipation, hemorrhoids, red or bleeding gums, redness or sores in mouth, change in taste, changes in hearing or ringing in ears, thirst, changed behaviour or aggressive behaviour (sometimes directed against others), feeling sleepy, cold sores, fungal or bacterial infections, irritation of prostate gland, increased need to pass urine, ear or respiratory infections, sinusitis, stuffy or runny nose, abnormal hair texture, sensitivity to sunlight, migraine headache, eye pain or infection, blurred vision, puffy face, puffy hands or feet, enlarged liver, problem affecting ovary or vagina, pain in breast, difficulty in speaking and swollen glands.

Common side effects (seen in more than 1 in 100 people taking Nplate): • bone marrow disorder, including increased bone marrow fibres (reticulin); • trouble sleeping (insomnia); • dizziness; • tingling or numbness of the hands or feet (paraesthesia); • migraine; • redness of the skin (flushing); • blood clot in a lung artery (pulmonary embolism); • nausea; • diarrhoea; • abdominal pain; • indigestion (dyspepsia); • constipation; • itching of the skin (pruritis); • bleeding under the skin (ecchymosis); • bruising (contusion); • rash; • joint pain (arthralgia); • muscles pain or weakness (myalgia); • pain in your hands and feet; • muscle spasm; • back pain; • bone pain; • tiredness (fatigue); • injection site bruising; • injection site pain; • injection site swelling; • swelling in the hands and feet (oedema peripheral); • flu like symptoms (influenza like illness); • pain; • weakness (asthenia); • fever (pyrexia); • chills; • contusion; • low blood platelet count (thrombocytopenia) and low blood platelet count (thrombocytopenia) after stopping Nplate; • higher than normal platelet counts (thrombocytosis).

Commonly reported side effects (at least 1 in every 100 patients, but less than 1 in every 10 patients): thirst, dehydration, high blood pressure, migraines, swollen glands, flushing, menstrual problems, decreased sexual drive, vaginal problem, breast pain, pain in testicle, problems with thyroid gland, red gums, dry mouth, red or sore mouth or tongue, tooth ache or tooth disorder, herpes simplex (fever blisters), taste change, upset stomach, dyspepsia (heartburn), constipation, enlargement of liver (liver problems, sometimes severe), loose stools, bedwetting in children, inflammation of the sinuses, bronchitis, eye pain, problem with your tear ducts, conjunctivitis (“pink eye”), agitation, sleepiness, sleepwalking, problem with behaviour, nervousness, stuffy or runny nose, sneezing, rapid breathing, pale or reddened skin, bruising, fingers and toes very sensitive to cold, problem with skin or nails, psoriasis (new or worsened), increased sweating, increased need to pass urine, fine shaking movements, decreased sensitivity to touch, arthritis.  Uncommonly reported side effects (at least 1 in every 1000 patients, but less than 1 in every 100 patients): bacterial infection and feeling of pins and needles.

Uncommon (in more than 1 in 1000 patients but less than 1 in 100patients): • serious infections (including tuberculosis, histoplasmosis and sepsis [blood poisoning]), joint infection; • skin infections, skin warts, superficial fungal infections; • anaemia, low white blood cell and platelet counts, lymphopaenia (low immune cell counts); • swelling of the lymph nodes; • systemic lupus erythematosus; • allergic reactions, (including seasonal and medicines allergy); • increased lipid and uric acidvalues, appetite disorders; • anxiety, depression, feeling sleepy and difficulty sleeping, shaking; • taste disturbances; • vision disturbances, eye inflammation or infection; • ear discomfort; • sensation of heart beatingirregularly, high blood pressure, flushing; • asthma, shortness of breath, hoarseness; • abdominal symptoms (such as vomiting, constipation), rectal bleeding; • skin disorders (such as psoriasis, eczema or infections)itchy rash, slow wound healing, bruising, hair loss; • muscle weakness; • urinary disturbances (such as blood in urine, increased urinary frequency); • increased menstrual bleeding; • flu-like symptoms, chest pain, swelling of the feet; • accidental injury, impaired healing.

• Pneumonia, respiratory infection, urinary tract infection, infection, inflammation of the ear • Low white blood cell counts • Anorexia, increased appetite • Anger towards others, confusion, fluctuation in mood, depression, anxiety, nervousness, difficulty with thinking • Convulsions, jerky movements, difficulty with speaking, loss of memory, tremor, difficulty sleeping, headache, sensitive skin, decreased sensation, difficulty with coordination, unusual eye movement, increased, decreased or absent reflexes • Blurred vision, double vision • Vertigo • High blood pressure, flushing or dilation of blood vessels • Difficulty breathing, bronchitis, sore throat, cough, dry nose • Vomiting (being sick), nausea (feeling sick), problems with teeth, inflamed gums, diarrhoea, stomach pain, indigestion, constipation, dry mouth or throat, flatulence • Facial swelling, bruises, rash, itch, acne • Joint pain, muscle pain, back pain, twitching • Incontinence • Difficulties with erection • Swelling in the legs and arms or swelling that may involve the face, trunk and limbs, difficulty with walking, weakness, pain, feeling unwell, flu-like symptoms • Decrease in white blood cells, increase in weight • Accidental injury, fracture, abrasion

Uncommon side effects (these can affect from 1 to 10 users in 1,000 patients treated) • Throat inflammation. • Feeling agitated, feeling disorientated, feeling sleepy, having a poor quality of sleep, lack of motivation or increased yawning. • Tasting things differently than usual, disturbance in attention or spasms and involuntary movements of the muscles. • Weight loss or weight gain, burping, indigestion or gastroenteritis. • Inflammation of the liver that may cause abdominal pain, tiredness or yellow coloration of the skin. • Vertigo, tinnitus (perception of sound in the ear when there is no external sound, ear pain. • Larger pupils (the dark centre of the eye) or visual disturbance. • Flushing, increase in blood pressure, feeling cold in your fingers and/ or toes, feeling dizzy (particularly when standing up too quickly), fast or irregular heart beat, night sweats, cold sweats, shivering or fainting. • Changes in ejaculation, abnormal periods, including heavy or prolonged periods • Allergic reactions, increased tendency to bruise, blisters or sensitivity to sunlight. • Muscle twitching. • Need to pass urine during the night or difficulty or inability to pass urine. • Grinding of teeth, dehydration, feeling hot/ cold, thirst, throat tightness or nose bleeds • Increased level of cholesterol in the blood.

29 Immune System Disorders Drug hypersensitivity Metabolism and Nutrition Disorders Anorexia, Polydipsia Psychiatric Disorders Confusional state, Listless, Anorgasmia, Blunted affect Nervous System Disorders Unresponsive to stimuli, Loss of consciousness, Neuroleptic malignant syndrome, Diabetic coma, Cerebrovascular accident, Depressed level of consciousness, Cerebral ischemia, Cerebrovascular disorder, Transient ischemic attack, Dysarthria, Disturbance in attention, Balance disorder, Speech disorder, Coordination abnormal, Movement disorder Eye Disorders Ocular hyperemia, Eye discharge, Eye swelling, Dry eye, Lacrimation increased, Photophobia, Visual acuity reduced, Eye rolling, Glaucoma Ear and Labyrinth Disorders Tinnitus Vascular Disorders Flushing Respiratory, Thoracic, and Mediastinal Disorders Wheezing, Pneumonia aspiration, Pulmonary congestion, Respiratory disorder, Rales, Epistaxis, Respiratory tract congestion, Hyperventilation, Dysphonia Gastrointestinal Disorders Dysphagia, Faecal incontinence, Faecaloma, Lip swelling, Cheilitis Skin and Subcutaneous Tissue Disorders Skin lesion, Skin disorder, Skin discoloration, Seborrheic dermatitis, Hyperkeratosis, Dandruff, Erythema Musculoskeletal, Connective Tissue, and Bone Disorders Rhabdomyolysis, Joint swelling, Posture abnormal, Joint stiffness Renal and Urinary Disorders Enuresis, Dysuria, Pollakiuria Reproductive System and Breast Disorders Ejaculation disorder, Vaginal discharge, Menstrual disorder General Disorders and Administration Site Conditions Generalised oedema, Face oedema, Gait disturbance, Thirst, Chills, Peripheral coldness, Drug withdrawal syndrome

Commonly reported side effects (at least 1 in every 100 patients, but less than 1 in every 10 patients): pain at the place of injection, increased sweating, flushing, chest pain, fingers and toes very sensitive to cold, bruise, numbness or tingling feeling, shaky hands, increased or decreased sensitivity to touch, swelling due to a build-up of excess water, increase in muscle movement, changes in your voice, ear infection, abnormal vision, eye pain or infection, dry or teary eyes, nervousness, aggressive behaviour, wanting to harm yourself, lack of interest, feeling confused, feeling anxious or nervous, difficulty concentrating, behaviour disorder, weakness, feeling sleepy, unusual dreams, sleepwalking, trouble sleeping, change in thyroid gland activity (which may make you feel tired or, less commonly, energetic), pain on the right side around your ribs, abnormal liver function, sores in mouth, sore tongue, toothache, tooth disorder, tooth abscess, increased appetite, stomach upset, constipation, loose stools, acid reflux, gastroesophageal or rectal disorder, urinary tract infection, bedwetting, incontinence, urination disorders, difficult, irregular, or no menstrual period, abnormally heavy and prolonged menstrual periods, disorder of vagina, testis pain, fever blisters, fungal infections, bacterial infections, swollen glands, respiratory infections, sneezing, rapid breathing, nose bleed, cough, stuffy or runny nose, shortness of breath, nose irritation, skin sensitive to sunlight, pale skin, redness of skin or skin disorder, eczema (inflamed, red, itchy and dryness of the skin with possible oozing lesions), rash with raised spotted lesions, acne, itching, dry skin, skin discolouration, skin wound, nail disorder, tumor (unspecified), decrease in the number of blood clotting cells, excess of uric acid (as in gout) in the blood, inflammation of the membrane of the stomach and intestine, inflammation of the vagina, development of male body traits, and excess of triglycerides in the blood.

Commonly reported side effects (at least 1 in every 100 patients, but less than 1 in every 10 patients): pain at the place of injection, increased sweating, flushing, chest pain, fingers and toes very sensitive to cold, bruise, numbness or tingling feeling, shaky hands, increased or decreased sensitivity to touch, swelling due to a build-up of excess water, increase in muscle movement, changes in your voice, ear infection, abnormal vision, eye pain or infection, dry or teary eyes, nervousness, aggressive behaviour, wanting to harm yourself, lack of interest, feeling confused, feeling anxious or nervous, difficulty concentrating, behaviour disorder, weakness, feeling sleepy, unusual dreams, sleepwalking, trouble sleeping, change in thyroid gland activity (which may make you feel tired or, less commonly, energetic), pain on the right side around your ribs, abnormal liver function, sores in mouth, sore tongue, toothache, tooth disorder, tooth abscess, increased appetite, stomach upset, constipation, loose stools, acid reflux, gastroesophageal or rectal disorder, urinary tract infection, bedwetting, incontinence, urination disorders, difficult, irregular, or no menstrual period, abnormally heavy and prolonged menstrual periods, disorder of vagina, testis pain, fever blisters, fungal infections, bacterial infections, swollen glands, respiratory infections, sneezing, rapid breathing, nose bleed, cough, stuffy or runny nose, shortness of breath, nose irritation, skin sensitive to sunlight, pale skin, redness of skin or skin disorder, eczema (inflamed, red, itchy and dryness of the skin with possible oozing lesions), rash with raised spotted lesions, acne, itching, dry skin, skin discolouration, skin wound, nail disorder, tumour (unspecified), decrease in the number of blood clotting cells, excess of uric acid (as in gout) in the blood, inflammation of the membrane of the stomach and intestine, inflammation of the vagina, development of male body traits, and excess of triglycerides in the blood.

Uncommon (affecting less than one person in 100 but more than one person in 1,000): • Anaemia, red or brownish spots on the skin (sometimes especially on the feet, legs, arms and buttocks, with joint pain, swelling of the hands and feet and stomach pain), bruising, reduction in white blood cells, clotting problems and bruising, • Loss of appetite, increased uric acid levels or frank gout, increased blood sugar levels, abnormal blood electrolyte levels, • Anxiety, nervousness, panic disorder (recurring panic attacks), confusion, depression, abnormal dreams, sleep disorders, sleepiness, memory impairment, • Pins and needles or similar sensations, pain in the extremities, trembling, migraine, fainting, • Blurred vision, burning or stinging in the eyes, conjunctivitis, worsening eyesight, seeing things in yellow, • Ringing, buzzing, roaring or clicking in the ears, • Low blood pressure, which may be associated with changes in posture (feeling light-headed or weak when you stand up, angina (chest pain), abnormal heartbeat, cerebrovascular accident (TIA, “ mini-stroke”), heart attack, palpitations, • Inflammation of blood vessels, which is often associated with a skin rash or bruising, • Sore throat, breathlessness, bronchitis, pneumonia, water on the lungs (which causes difficulty breathing), nosebleed, runny nose, congestion, • Constipation, wind, stomach upsets, stomach spasms, vomiting, dry mouth, inflammation of a salivary gland, toothache, • Jaundice (yellowing of the eyes and skin), inflammation of the pancreas, • Hives, itching, inflammation of the skin, rash, redness of the skin, sensitivity to light, dry skin, flushing, sweating, hair loss, • Pain in the arms, shoulders, hips, knees or other joints, joint swelling, stiffness, muscle weakness, • Frequent urination including at night, abnormal kidney function including inflammation of the kidneys, urinary infection, sugar in the urine, • Decreased sexual appetite, impotence, • Swelling of the face, fever.

Cardiac failure aggravated, arrhythmia, syncope, bradycardia, cyanosis, palpitation Rare: Tachycardia Unknown: Cardiac failure, pericardial effusion Vascular disorders Common: Flushing Uncommon: Hypotension, peripheral ischaemia, hypertension, thrombophlebitis, haematoma, ecchymosis, petechia, vasospasm, hot flush Rare: Circulatory failure Respiratory, thoracic and mediastinal disorders Common: Lower respiratory tract infection (e. g. bronchitis, pneumonia), upper respiratory tract infection, sinusitis, dyspnoea Uncommon: Pulmonary oedema, bronchospasm, pleurisy, epistaxis Rare: Pleural effusion Unknown: Interstitial lung disease (including rapidly progressive disease, lung fibrosis and pneumonitis) Gastrointestinal disorders Common: Abdominal pain, diarrhoea, nausea, dyspepsia Uncommon: Diverticulitis, gastroesophageal reflux, constipation, cheilitis Rare: Intestinal perforation, gastrointestinal haemorrhage, intestinal stenosis Unknown: Pancreatitis Hepatobiliary disorders Common: Transaminases increased Uncommon: Cholecystitis, hepatic function abnormal Rare: Hepatitis Unknown: Liver failure, autoimmune hepatitis, hepatocellular damage, jaundice Skin and subcutaneous tissue disorders Common: Urticaria, rash, pruritus, hyperhidrosis, dry skin Uncommon: Bullous eruption, furunculosis, fungal dermatitis, onychomycosis, eczema, seborrhoea, rosacea, skin papilloma, hyperkeratosis, alopecia, abnormal skin pigmentation Unknown: Toxic epidermal necrolysis, Stevens-Johnson-Syndrome, psoriasis, including new onset and pustular (primarily palm & soles), erythema multiforme Musculoskeletal and connective tissue disorders Uncommon: Arthralgia, myalgia, back pain Renal and urinary disorders Uncommon: Pyelonephritis, urinary tract infection Reproductive system and breast disorders Uncommon: Vaginitis General disorders and administration site conditions Common: Infusion-related reaction, chest pain, fatigue, fever Uncommon: Impaired healing, injection site reaction, chills, oedema, pain Rare: Granulomatous lesion Investigations Uncommon: Autoantibody positive, complement factor abnormal

110 Uncommon (affects 1 to 10 users in 1000): • Excessive drinking of water, stool incontinence, thirsty, very hard faeces, hoarseness or voice disorder • Lung infection caused by inhaling of food into the breathing passages, bladder infection, ‘ pink eye’, sinus infection, viral infection, ear infection, tonsil infection, infection under the skin, eye infection, stomach infection, eye discharge, yeast infection of nails • Abnormal electrical conduction of the heart, drop in blood pressure after standing, low blood pressure, feeling dizzy after changing body position, abnormal electric activity tracing of the heart (ECG), abnormal heart rhythm, awareness of heart beating, heart rate increased or decreased • Urinary incontinence, pain when passing urine, frequent passing of urine • Confused, disturbance in attention, low level of consciousness, excessive sleep, nervousness, elated mood (mania), lack of energy and interest • Blood sugar increased, liver enzymes increased, white blood cell count decreased, low haemoglobin or red blood cell count (anaemia), increase in eosinophils (special white blood cells), blood creatinine phosphokinase increased, decrease in platelets (blood cells that help you stop bleeding) • Muscle weakness, muscle pain, ear pain, neck pain, joint swelling, abnormal posture, joint stiffness, musculoskeletal chest pain, chest discomfort • Skin lesion, skin disorder, dry skin, intense itching of skin, acne, hair loss, skin inflammation caused by mites, skin discoloration, thickening of skin, flushing, reduced skin sensitivity to pain or touch, inflammation of oily skin • No menstruation, sexual dysfunction, erectile dysfunction, ejaculation disorder, breast discharge, enlargement of breast in men, decreased sexual drive, irregular menstruation, vaginal discharge • Fainting, gait disturbance, sluggishness, decreased appetite resulting in malnutrition and low body weight, feeling ‘ out of sorts’, balance disorder, allergy, edema, speech disorder, chills, abnormal coordination • Painful oversensitivity to light, increased blood flow to the eye, eye swelling, dry eye, increase in tears • Breathing passage disorder, lung congestion, crackly lung noise, congestion of breathing passages, trouble speaking, difficulty swallowing, cough with sputum, coarse/ whistling sound during breathing, flu-like illness, sinus congestion • Unresponsive to stimuli, loss of consciousness, sudden swelling of lips and eyes along with difficulty breathing, sudden weakness or numbness of the face, arms, or legs, especially on one side, or instances of slurred speech that last for less than 24 hours (these are called mini-strokes or strokes), involuntary movements of face, arms, or legs, ringing in ears, face edema.