Adverse events were poorly and inconsistently reported by the Primary Systematic Review and the Supplementary Evidence Review; therefore this guideline has presented selected information from the Therapeutic Goods Administration (August 2016) regarding the safety of pharmaceuticals commonly used by women who have had breast cancer, including the pharmaceuticals assessed by the Primary Evidence Base. For full details on the safety of these drugs, see the product information on the Australia Register of Therapeutic Goods website.
Table 2. Selected safety information from the Australia Register of Therapeutic Goods approved product information (August 2016) on pharmaceuticals used by women with a history of breast cancer 101
| Generic name (brand names) | Indications | Contraindications | Common side effects (occurring in ≥1% of patients) | Drug interactions | Precautions / Comments |
|---|---|---|---|---|---|
|
Breast cancer |
Pregnancy or lactation |
Hot flushes Asthenia Headache Nausea Vomiting Rash Weakness Joint pain, stiffness / arthritis Vaginal dryness and bleeding Hair thinning (alopecia), Allergic reactions Diarrhoea Somnolence Carpel Tunnel Syndrome Sensory disturbances Increases in liver enzymes Anorexia Hypercholesterolaemia Bone pain Myalgia |
Drugs metabolised by cytochrome P450 1A2, 2C8/9, 3A4 Tamoxifen
|
Not recommended for use in children or in pre-menopausal women. Potential risks associated with patients with renal and hepatic impairment. May cause a reduction in bone mineral density, therefore women with osteoporosis or at risk of osteoporosis should be monitored. Should not be co-administered with oestrogen-containing products as these would negate its pharmacological action.
|
|
|
|
Nicotine dependence |
Seizure disorders CNS tumour Abrupt withdrawal from benzodiazepines or alcohol Current or previous diagnosis of bulimia or anorexia nervosa Monoamine oxidase inhibitors (MAOIs) |
Fever Asthenia Insomnia Headache Dizziness Agitation, anxiety Tremor Concentration disturbance Depression Dry mouth Gastrointestinal disturbance Abdominal pain Constipation Hypersensitivity reactions Visual disturbance Taste disorders
|
May interact with drugs known to affect the CYP2B6 isoenzyme Drugs which require activation by CYP2D6 (e.g. tamoxifen) may have reduced efficacy Co-administration of drugs known to induce (e.g. carbamazepine, phenobarbital) or inhibit (e.g. valproate) metabolism may affect its activity
|
Bupropion is associated with a dose-related risk of seizures, therefore the recommended dose must not be exceeded. Used with caution in patients with renal and hepatic impairments and used with extreme caution in patients with severe hepatic cirrhosis. Care and monitoring should be taken for the emergence of significant depressive symptoms or suicidal ideation in patients, especially patients with a history of psychiatric illness . Care should be taken in patients with a recent history of myocardial infarction or unstable heart disease. |
|
|
Major depression Obsessive-compulsive disorder |
Monoamine oxidase inhibitors Linezolid Pimozide Congenital long QT syndrome |
Migraine Abnormal accommodation Taste perversion Amnesia Apathy Depression Increased appetite Aggravated depression Saliva increased Increased / decreased weight Postural hypotension, hypotension Tachycardia Polyuria Amenorrhoea Sweating Drowsiness Dry mouth Nausea |
Drugs that prolong the QT interval Selegiline (selective MAO-B inhibitor) Pimozide Serotonergic drugs Hepatic enzymes
|
Clinical worsening and suicide risk associated with psychiatric disorders Care, monitoring and more frequent ECG monitoring should be taken with patients at higher risk of developing prolongation of the QT interval. Caution should be taken in patients concomitantly treated with oral anticoagulants, medicinal products known to affect platelet function as well as in patients with a past history of abnormal bleeding or predisposing conditions. Used with caution in patients with a history of seizures. Care should be taken with diabetic patients as their insulin and glucose responses may be modified. Care should be taken with elderly patients who are a group at risk of hyponatraemia Review use and dose if patients develop akathisia within the first few weeks of treatment. Withdrawal symptoms when treatment is discontinued are common |
|
|
Hypertension Renal hypertension Migraine prophylaxis Menopausal flushing |
Bradyarrhythmia |
Dizziness Sedation Orthostatic hypotension Dry mouth Depression Sleep disorder Dizziness, sedation Headache Constipation Nausea Salivary gland pain Vomiting Erectile dysfunction Fatigue
|
Antihypertensive agents Nonsteroidal anti-inflammatory drugs can reduce the therapeutic effect of clonidine Substances with α2-adrenergic receptor blocking properties (e.g. phentolamine), may abolish the α2-adrenergic receptor mediated effects of clonidine in a dose-dependent way Concomitant administration of drugs with a negative chronotropic or dromotropic effect (i.e. β-blockers or digitalis glycosides) can cause bradycardiac rhythm disturbances Tricyclic antidepressants or neuroleptics with -receptor blocking effects |
Special care should be exercised in treating patients who have a history of depression or who have advanced cerebrovascular disease. Diabetic patients should be monitored for a possible increase in their requirements of anti-diabetic therapy. Caution should be used in patients with mild to moderate bradyarrhythmia such as low sinus rhythm, with disordered of cerebral or puerperal perfusion, polyneuropathy and constipation. Careful consideration for dosage is required in patients with renal insufficiency. Monitoring is required in patients with heart failure or severe coronary heart disease Termination of oral therapy should be gradual. Warnings should be given to patients who wear contact lenses that treatment may cause decreased lacrimation.
|
|
|
Major depression, including the prevention of relapse |
Monoamine oxidase inhibitors
|
Very common (>10%) Nausea Dry Mouth Constipation Fatigue Dizziness Headache Insomnia Hyperhidrosis
*for side effects occurring in between 1% and 10% of patients please see specific PI
|
Monoamine oxidase inhibitors Caution advised for CNS-active drugs Other agents that affect the serotonergic neurotransmitter system (including triptans, SSRIs, other SNRIs etc.)
|
Clinical worsening and suicide risk associated with psychiatric disorders. Used cautiously in patients with a history or family history of mania or hypomania. The development of syndromes like serotonin syndrome (SS) or Neuroleptic Malignant Syndrome (NMS) may occur. Close monitoring of patients with raised intra-ocular pressure or patients at risk for acute narrow-angle glaucoma. All patients should have regular monitoring of blood pressure. With caution exercised in treating patients with underlying conditions that might be compromised by increases in blood pressure. Caution is advised for patients with cardiovascular, cerebrovascular, or lipid metabolism disorders due to increases in blood pressure and heart rate. Risk of bleeding events associated with concomitantly using drugs that affect coagulation or bleeding (e.g. NSAIDs, aspirin) Care should be taken with elderly patients or patients taking diuretics who are a group at risk of hyponatraemia. |
|
|
Major depression Social anxiety disorder (social phobia) General anxiety disorder Obsessive compulsive disorder |
Escitalopram or any of the excipients Monoamine oxidase inhibitors Pimozide |
Nausea Headache Insomnia Diarrhoea Dry mouth Dizziness Somnolence Anorexia Libido decreased Appetite decreased Agitation Impotence Yawning Fatigue Sweating Anorgasmia Ejaculation disorder / failure |
Monoamine oxidase inhibitors serotonergic agents Pimozide |
Clinical worsening and suicide risk associated with psychiatric disorders. Review use and dose if patients develop akathisia within the first few weeks of treatment. Caution should be taken in patients concomitantly treated with oral anticoagulants, medicinal products known to affect platelet function as well as in patients with a past history of abnormal bleeding or predisposing conditions. Care should be taken with elderly patients who are a group at risk of hyponatraemia Used with caution in patients with a history of seizures. Care should be taken with diabetic patients as their insulin and glucose responses may be modified. Used cautiously in patients with a history or family history of mania or hypomania.
|
|
Oestrogen receptor-positive breast cancer |
Pregnancy or lactation |
Very common (>10%) Pain Fatigue Abdominal pain Nausea Hepatic enzyme increased (including ALT increased, GGT increased) Blood bilirubin increased Serum alkaline phosphatase increase Dizziness Headache Depression Insomnia Hot flushes Sweating Lymphocyte decrease
*for side effects occurring in between 1% and 10% of patients please see specific PI |
No formal drug interaction studies have been carried out |
Should not be co-administered with oestrogen-containing products as these would negate its pharmacological action. Should not be administered to women with premenopausal endocrine status. Care and monitoring should be taken with women who have/at risk of osteoporosis as bone mineral density and fracture risk may be impacted.
|
|
|
|
Major depression Obsessive compulsive disorder Premenstrual dysphoric disorder (PMDD) |
Monoamine oxidase inhibitors Should not be used in combination with Pimozide
|
Very common (>10%)* Fatigue (includes asthenia) Diarrhoea Nausea Anxiety and nervousness Dizziness Headache Insomnia Somnolence Tremor
*for side effects occurring in between 1% and 10% of patients please see specific PI |
Tryptophan, Warfarin, Pimozide, Serotonergic drugs Drugs metabolised by cytochrome P450 3A4 and P450 (CYP2D6) Highly protein bound drugs Tamoxifen may have reduced efficacy |
Clinical worsening and suicide risk associated with psychiatric disorders. Possibility of fractures should be considered during treatment. The development of serotonin syndrome may occur. Caution should be taken for patients with conditions such as congenital long QT syndrome; acquired long QT syndrome; a family history of QT prolongation; or other conditions that predispose to arrhythmias or increased exposure to fluoxetine . Care should be taken with patients with a history of seizures. Caution should be taken for patients with concomitant illness, especially diseases or conditions that could affect metabolism or haemodynamic responses (e.g. recent history of myocardial infarction, cirrhosis of the liver, renal impairment, diabetes, acute narrow-angle glaucoma, abnormal bleeding). |
|
|
Epilepsy Neuropathic pain |
Hypersensitivity to gabapentin |
Side effects occurring in >5% of participants* Fatigue Nausea Vomiting Somnolence Dizziness Ataxia Nystagmus Headache Tremor Diplopia Asthenia Diarrhoea Peripheral oedema
*for side effects occurring in between 1% and 5% of patients please see specific PI |
Cimetidine Antacids may reduce gabapentin bioavailability |
Antiepileptic drugs, including gabapentin, increase the risk of suicidal thoughts or behaviours in patients taking these drugs for any indication. Caution should be taken in patients who have mixed seizure disorders that include absence seizures.
|
|
|
Hormone receptor positive breast cancer in postmenopausal women |
Premenopausal endocrine status Pregnancy Lactation |
Very common (>10%)* High cholesterol / Hypercholesterolaemia Hot flushes Increased sweating Arthralgia Fatigue (including asthenia and malaise)
*for side effects occurring in between 1% and 10% of patients please see specific PI |
There is minimal data on the interaction between Letrozole and other drugs. Metabolism of Letrozole may be influenced by drugs known to affect the CYP3A4 and CYP2A6 enzymes. |
Caution and supervision of patients with renal and hepatic impairment. Should not be co-administered with tamoxifen, other anti-estrogens or estrogen-containing therapies as these may diminish the pharmacological action. Monitoring of overall bone health is recommended during treatment. |
|
|
Palliative treatment of recurrent inoperable or metastatic carcinoma of the breast |
As a diagnostic test for pregnancy |
Weight gain Increased appetite Nausea Vomiting Edema Breakthrough uterine bleeding |
No information is available regarding interactions with food, alcohol or other drugs |
Use with caution in patients with a history of thromboembolic disease or diabetes mellitus. Not recommended for use during the first four months of pregnancy. |
|
|
Major depression Obsessive compulsive disorder Panic disorder Social anxiety disorder/Social Phobia Generalised Anxiety Disorder Post-traumatic Stress Disorder |
Monoamine oxidase inhibitors Should not be used in combination with Pimozide or Thioridazine |
The most commonly observed adverse events associated with use and not seen at an equivalent incidence among placebo treated patients: Nausea Somnolence Sweating Tremor Asthenia Dry mouth Insomnia Sexual dysfunction Dizziness Constipation Diarrhoea Decreased appetite
For further side effects please see specific PI. |
Medicines that interfere with haemostasis (NSAIDs, aspirin, warfarin etc.)
Drugs affecting hepatic metabolism Drugs metabolised by cytochrome P450 3A4/2D6 Serotonergic drugs Tamoxifen may have reduced efficacy |
Clinical worsening and suicide risk associated with psychiatric disorders. Caution and supervision of patients with renal/hepatic impairment and diabetes. Caution should be taken in the co-administration of tricyclic antidepressants. Used cautiously in patients with a history or family history of mania or hypomania. Possibility of fractures should be considered during treatment. Caution should be observed with patients with cardiac conditions, epilepsy, seizures and glaucoma. Caution should be taken in patients concomitantly treated with oral anticoagulants, medicinal products known to affect platelet function as well as in patients with a past history of abnormal bleeding or predisposing conditions. Care should be taken with elderly patients who are a group at risk of hyponatraemia.
|
|
|
Epilepsy Neuropathic pain |
Galactose intolerance Lapp lactase deficiency Glucose-galactose malabsorption |
Very common (>10%)* Dizziness Somnolence
*for side effects occurring in between 1% and 10% of patients please see specific PI
|
Pregabalin undergoes negligible metabolism in humans and is unlikely to produce pharmacokinetic interactions. |
Antiepileptic drugs, including gabapentin, increase the risk of suicidal thoughts or behaviours in patients taking these drugs for any indication. Caution should be taken for patients with congestive heart failure. |
|
|
Major depression Social anxiety disorder Premenstrual dysphoric disorder Obsessive compulsive disorder in children |
Monoamine oxidase inhibitors Pimozide
|
Very common (>10%)* Fatigue Tremor Nausea Insomnia Somnolence
*for side effects occurring in between 1% and 10% of patients please see specific PI
|
Pimozide Drugs that prolong the QT interval Serotonergic drugs Medicines that interfere with haemostasis Drugs highly bound to plasma proteins Drugs metabolised by CYP enzymes
|
The development of syndromes like serotonin syndrome or Neuroleptic Malignant Syndrome has been reported Clinical worsening and suicide risk associated with psychiatric disorders. Caution should be taken in patients concomitantly treated with oral anticoagulants, medicinal products known to affect platelet function as well as in patients with a past history of abnormal bleeding or predisposing conditions. Care should be taken with elderly patients who are a group at risk of hyponatraemia. Possibility of fractures should be considered during treatment. Caution should be observed with patients with diabetes, seizures and glaucoma. |
|
|
Breast cancer |
Pregnancy |
Hot flushes Nausea and vomiting |
Coumarin type anticoagulants Cytotoxic agents Rifampicin CYP2D6 inhibitors Fluoxetine and Paroxetine |
An increased incidence of endometrial changes including hyperplasia, polyps and cancer and uterine sarcoma (mostly malignant mixed Mullerian tumours) has been reported. Used cautiously in patients with existing leucopenia or thrombocytopenia. |
|
|
Male hypogonadism Male testosterone deficiency |
Suspected carcinoma of the prostate or breast (in men) Pregnancy and lactation Patients with nephrosis or nephrotic phase of nephritis Hypercalcaemis accompanying malignant tumours |
Very common (>10%) Administration site reactions
Common (>1% and <10%) Headache Prostatic disorders Gynaecomastia Mastodynia Dizziness Paraesthesia Amnesia Hyperaesthesia Mood disorders Hypertension Diarrhoea Alopecia Urticaria |
Insulin Anticoagulants Corticosteroids Oxyphenbutazone Cyclosporin Barbiturates and other enzyme inducers |
Androgens may accelerate the progression of sub-clinical prostate cancer and benign prostatic hyperplasia. Care and monitoring should be taken for patients with myocardial or renal dysfunction, hypertension, migraine, diabetes or epilepsy due to fluid retention. |
|
|
Menopause symptoms Bone mineral density loss |
Known, suspected or history of breast cancer Estrogen-dependent malignant tumours Pregnancy and lactation Undiagnosed genital bleeding Untreated endometrial hyperplasia Previous or current venous thromboembolism, thrombophilic disorders, Any history of arterial thromboembolic disease Liver disease Porphyria |
None occurring with an incidence of at least 10% Common (>1% and <10%) Lower abdominal pain Abnormal hair growth Genital discharge Endometrial wall thickening Postmenopausal or vaginal Hemorrhage Breast tenderness Genital pruritus Vaginal candidiasis Pelvic pain Cervical dysplasia Vulvovaginitis |
May enhance the effect of anticoagulants CYP3A4 substrates CYP3A4 inducing compounds St John’s Wort
|
Tibolone increases the risk of ischaemic stroke from the first year of treatment. Care and monitoring should be taken for women with conditions such as Leiomyoma or endometriosis, risk factors for thromboembolic disorders and estrogen dependent tumours, hypertensions, liver disorders, diabetes, chloelithiasis, migraines, systemic lupus erythematosus, history of endometrial hyperplasia, epilepsy, asthma and otosclerosis.
|
|
|
Climacteric symptoms |
Pregnancy and lactation Known, suspected or history of breast cancer Other undiagnosed breast pathology Oestrogen-dependent neoplasia Abnormal genital bleeding Venous thromboembolism, Arterial thromboembolic disease, Severe uncontrolled hypertension Liver dysfunction |
Very common (>10%) Breast pain
Common (>1% and <10%) Abnormal uterine bleeding Tenderness Enlargement Discharge Leucorrhoea Arthralgias Leg cramp Alopecia Changes in weight Increased triglycerides Vaginitis Depression
|
CYP3A4 inducers or inhibitors St John’s Wort Antihypertensive agents |
Increases the risk of stroke, deep vein thrombosis and pulmonary embolism. The use of unopposed oestrogens in women with an intact uterus has been associated with an increased risk of endometrial cancer. Caution and monitoring of patients with a history of cardiac or renal dysfunction due to fluid retention.
|
|
|
Major depression General anxiety disorder Social anxiety disorder Panic disorder |
Monoamine oxidase inhibitors
|
None occurring with an incidence of at least 10%
Common(>1% and <10%) Headache, Nausea Insomnia, Drowsiness Asthenia / fatigue Hypertension, vasodilation Appetite decreased Vomiting Serum cholesterol increased Weight loss Abnormal dreams Dry mouth Paraesthesia Tremor Yawning Abnormality of accommodation, mydriasis Visual disturbance Anorgasmia Urination impaired Dizziness, Weakness Constipation Sweating Nervousness |
Drugs that prolong the QT interval Monoamine oxidase inhibitors Other agents that affect the serotonergic neurotransmitter system (including triptans, SSRIs, other SNRIs etc.) St John’s Wort
|
Clinical worsening and suicide risk associated with psychiatric disorders. The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome-like reaction may occur. Caution should be observed with patients with diabetes, hypertension, unstable heart disease and glaucoma. Caution should be taken for patients with risk factors for QTc prolongation. |
|
|
Insomnia |
Obstructive sleep apnoea Myasthenia gravis Severe hepatic insufficiency Severe pulmonary insufficiency Children under 18 years of age Prior or concomitant intake with alcohol |
Headache Drowsiness Dizziness Diarrhoea |
CNS depressants Imipramine Hepatic enzyme inhibitors and inducers
|
Continuous long-term use of Zolpidem is not recommended and should not exceed four weeks. Care should be taken in patients with hepatic, renal, memory impairment. |