Drug reference
Telotristat ethyl and its active metabolite inhibit L-tryptophan hydroxylases TPH-1 and TPH-2 which reduces the production of serotonin, thereby alleviating symptoms associated with carcinoid syndrome.
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Carcinoid syndrome diarrhoea (specialist use only) ▶BY MOUTH ▶Adult: 250 mg 3 times a day, review treatment if no response after 12 weeks
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Scottish Medicines Consortium (SMC) decisions SMC No. 1327/18 The Scottish Medicines Consortium has advised (June 2018) that telotristat ethyl (Xermelo ®) is accepted for restricted use within NHS Scotland for the treatment of carcinoid syndrome diarrhoea in adults who experience an average of four or more bowel motions per day, despite receiving somatostatin analogue therapy. This advice is contingent upon the continuing availability of the patient access scheme in NHS Scotland or a list price that is equivalent or lower. All Wales Medicines Strategy Group (AWMSG) decisions AWMSG No. 2037 The All Wales Medicines Strategy Group has advised (July 2018) that telotristat ethyl (Xermelo ®) is recommended as an option for restricted use within NHS Wales for the treatment of carcinoid syndrome diarrhoea in adults who are inadequately controlled by somatostatin analogue therapy and who experience an average of four or more bowel movements a day. This recommendation applies only in circumstances where the approved Wales Patient Access Scheme (WPAS) is utilised or where the list/contract price is equivalent or lower than the WPAS price.
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→Appendix 1: telotristat ethyl
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▶Common or very common Appetite decreased. constipation . fatigue. fever. gastrointestinal discomfort. gastrointestinal disorders. headache. peripheral oedema
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Manufacturer advises avoid—toxicity in animal studies.
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Manufacturer advises avoid—no information available.
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Manufacturer advises caution in mild to moderate impairment; avoid in severe impairment (no information available). Dose adjustments Manufacturer advises consider dose reduction to 250 mg twice daily in mild impairment and to 250 mg once daily in moderate impairment, according to tolerability.
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Manufacturer advises caution in mild-to-moderate impairment; avoid in severe impairment—no information available.
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Manufacturer advises monitor liver function at initiation and during treatment as clinically indicated—discontinue if liver injury suspected.
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There can be variation in the licensing of different medicines containing the same drug. Tablet CAUTIONARY AND ADVISORY LABELS 3, 21 ▶Xermelo (Ipsen Ltd) A Telotristat ethyl 250 mg Xermelo 250mg tablets | 90 tablet P £1,120.00 Cytotoxic responsive malignancy Cytotoxic drugs Overview The chemotherapy of cancer is complex and should be confined to specialists in oncology. Cytotoxic drugs have both anti-cancer activity and the potential to damage normal tissue; most cytotoxic drugs are teratogenic. Chemotherapy may be given with a curative intent or it may aim to prolong life or to palliate symptoms. In an increasing number of cases chemotherapy may be combined with radiotherapy or surgery or both as either neoadjuvant treatment (initial chemotherapy aimed at shrinking the primary tumour, thereby rendering local therapy less destructive or more effective) or as adjuvant treatment (which follows definitive treatment of the primary disease, when the risk of subclinical metastatic disease is known to be high). All cytotoxic drugs cause side-effects and a balance has to be struck between likely benefit and acceptable toxicity. Combinations of cytotoxic drugs, as continuous or pulsed cycles of treatment, are frequently more toxic than single drugs but have the advantage in certain tumours of enhanced response, reduced development of drug resistance and increased survival. However for some tumours, single- agent chemotherapy remains the treatment of choice. Cytotoxic drugs fall into a number of classes, each with characteristic antitumour activity, sites of action, and toxicity. A knowledge of sites of metabolism and excretion is important because impaired drug handling as a result of disease is not uncommon and may result in enhanced toxicity. Cytotoxic drug handling guidelines . Trained personnel should reconstitute cytotoxics . Reconstitution should be carried out in designated pharmacy areas . Protective clothing (including gloves, gowns, and masks) should be worn . The eyes should be protected and means of first aid should be specified . Pregnant staff should avoid exposure to cytotoxic drugs (all females of child-bearing age should be informed of the reproductive hazard) . Use local procedures for dealing with spillages and safe disposal of waste material, including syringes, containers, and absorbent material . Staff exposure to cytotoxic drugs should be monitored Intrathecal chemotherapy A Health Service Circular (HSC 2008/001) provides guidance on the introduction of safe practice in NHS Trusts where intrathecal chemotherapy is administered; written local guidance covering all aspects of national guidance should be available. Support for training programmes is also available. Copies, and further information may be obtained from the Department of Health and Social Care website (www.gov.uk/ government/organisations/department-of-health-and-social- care). Safe systems for cytotoxic medicines NHS cancer networks have been established across the UK to bring together all stakeholders in all sectors of care, to work collaboratively to plan and deliver high quality cancer services for a given population. NHS cancer networks have websites containing information on local chemotherapy services and treatment. Safe system requirements: . cytotoxic drugs for the treatment of cancer should be given as part of a wider pathway of care coordinated by a multidisciplinary team . cytotoxic drugs should be prescribed, dispensed, and administered only in the context of a written protocol or treatment plan . injectable cytotoxic drugs should only be dispensed if they are prepared for administration . oral cytotoxic medicines should be dispensed with clear directions for use Cytotoxic drugs: important safety information Risk of incorrect dosing of oral anti-cancer medicines The National Patient Safety Agency has advised (January 2008) that the prescribing and use of oral cytotoxic medicines should be carried out to the same standard as parenteral cytotoxic therapy. . non-specialists who prescribe or administer on-going oral cytotoxic medication should have access to written protocols and treatment plans, including guidance on the monitoring and treatment of toxicity; . staff dispensing oral cytotoxic medicines should confirm that the prescribed dose is appropriate for the patient. Patients should have written information that includes details of the intended oral anti-cancer regimen, the treatment plan, and arrangements for monitoring, taken from the original protocol from the initiating hospital. Staff dispensing oral cytotoxic medicines should also have access to this information, and to advice from an experienced cancer pharmacist in the initiating hospital. Cytotoxic drug doses Doses of cytotoxic drugs are determined using a variety of different methods including body-surface area or body- weight. Alternatively, doses may be fixed. Doses may be further adjusted following consideration of a patient’s neutrophil count, renal and hepatic function, and history of previous adverse effects to the cytotoxic drug. Doses may also differ depending on whether a drug is used alone or in combination. Because of the complexity of dosage regimens in the treatment of malignant disease, dose statements have been omitted from some of the drug entries in this chapter. Immune system and malignant disease However, even where dose statements have been provided, detailed specialist literature, individual hospital chemotherapy protocols, or local cancer networks should be consulted before prescribing, dispensing, or administering cytotoxic drugs. Prescriptions should not be repeated except on the instructions of a specialist. Cytotoxic drug side-effects Side-effects common to most cytotoxic drugs are discussed below whilst side-effects characteristic of a particular drug or class of drugs (e.g. neurotoxicity with vinca alkaloids) are mentioned in the appropriate sections. Manufacturers’ product literature, hospital-trust protocols, and cancer- network protocols should be consulted for full details of side-effects associated with individual drugs and specific chemotherapy regimes. Many side-effects of cytotoxic drugs often do not occur at the time of administration, but days or weeks later. It is therefore important that patients and healthcare professionals can identify symptoms that cause concern and can contact an expert for advice. Toxicities should be accurately recorded using a recognised scoring system such as the Common Toxicity Criteria for Adverse Events (CTCAE) developed by the National Cancer Institute. Extravasation of intravenous drugs A number of cytotoxic drugs will cause severe local tissue necrosis if leakage into the extravascular compartment occurs. To reduce the risk of extravasation injury it is recommended that cytotoxic drugs are administered by appropriately trained staff. See information on the prevention and management of extravasation injury. Oral mucositis A sore mouth is a common complication of cancer chemotherapy; it is most often associated with fluorouracil p. 961, methotrexate p. 963, and the anthracyclines. It is best to prevent the complication. Good oral hygiene (rinsing the mouth frequently and effective brushing of the teeth with a soft brush 2–3 times daily) is probably beneficial. For fluorouracil, sucking ice chips during short infusions of the drug is also helpful. Once a sore mouth has developed, treatment is much less effective. Saline mouthwashes should be used but there is no good evidence to support the use of antiseptic or anti- inflammatory mouthwashes. In general, mucositis is self- limiting but with poor oral hygiene it can be a focus for blood-borne infection. Tumour lysis syndrome Tumour lysis syndrome occurs secondary to spontaneous or treatment-related rapid destruction of malignant cells. Patients at risk of tumour lysis syndrome include those with non-Hodgkin’s lymphoma (especially if high grade and bulky disease), Burkitt’s lymphoma, acute lymphoblastic leukaemia and acute myeloid leukaemia (particularly if high white blood cell counts or bulky disease), and occasionally those with solid tumours. Pre-existing hyperuricaemia, dehydration, and renal impairment are also predisposing factors. Features include hyperkalaemia, hyperuricaemia (see below), and hyperphosphataemia with hypocalcaemia; renal damage and arrhythmias can follow. Early identification of patients at risk, and initiation of prophylaxis or therapy for tumour lysis syndrome, is essential. Hyperuricaemia Hyperuricaemia, which may be present in high-grade lymphoma and leukaemia, can be markedly worsened by chemotherapy and is associated with acute renal failure. Allopurinol p. 1183 should be started 24 hours before treating such tumours and patients should be adequately hydrated. The dose of mercaptopurine p. 963 or azathioprine p. 881 should be reduced if allopurinol needs to be given Immune system and malignant disease concomitantly. Febuxostat p. 1184 may also be used and should be started 2 days before cytotoxic therapy is initiated. Rasburicase p. 993, a recombinant urate oxidase, is licensed for hyperuricaemia in patients with haematological malignancy. It rapidly reduces plasma-uric acid concentration and may be of particular value in preventing complications following treatment of leukaemias or bulky lymphomas. Bone-marrow suppression All cytotoxic drugs except vincristine sulfate p. 980 and bleomycin p. 970 cause bone-marrow suppression. This commonly occurs 7 to 10 days after administration, but is delayed for certain drugs, such as carmustine p. 943, lomustine p. 947, and melphalan p. 948. Peripheral blood counts must be checked before each treatment, and doses should be reduced or therapy delayed if bone-marrow has not recovered. Cytotoxic drugs may be contra-indicated in patients with acute infection; any infection should be treated before, or when starting, cytotoxic drugs. Fever in a neutropenic patient (neutrophil count less than 1.066109/litre) requires immediate broad-spectrum antibacterial therapy. Appropriate bacteriological investigations should be conducted as soon as possible. Patients taking cytotoxic drugs who have signs or symptoms of infection should be advised to seek prompt medical attention. All patients should initially be investigated and treated under the supervision of the appropriate oncology or haematology specialist. In selected patients, the duration and the severity of neutropenia can be reduced by the use of recombinant human granulocyte-colony stimulating factors. Symptomatic anaemia is usually treated with red blood cell transfusions. For guidance on the use of erythropoietins in patients with cancer, see MHRA/CHM advice and NICE guidance. Alopecia Reversible hair loss is a common complication, although it varies in degree between drugs and individual patients. No pharmacological methods of preventing this are available. Thromboembolism Venous thromboembolism can be a complication of cancer itself, but chemotherapy increases the risk. Cytotoxic drugs: effect on pregnancy and reproductive function Most cytotoxic drugs are teratogenic and should not be administered during pregnancy, especially during the first trimester. Considerable caution is necessary if a pregnant woman presents with cancer requiring chemotherapy, and specialist advice should always be sought. Exclude pregnancy before treatment with cytotoxic drugs. Contraceptive advice should be given before cytotoxic therapy begins- women of childbearing age should use effective contraception during and after treatment. Regimens that do not contain an alkylating drug or procarbazine may have less effect on fertility, but those with an alkylating drug or procarbazine carry the risk of causing permanent male sterility (there is no effect on potency). Pretreatment counselling and consideration of sperm storage may be appropriate. Women are less severely affected, though the span of reproductive life may be shortened by the onset of a premature menopause. No increase in fetal abnormalities or abortion rate has been recorded in patients who remain fertile after cytotoxic chemotherapy. Cytotoxic drugs: nausea and vomiting Nausea and vomiting cause considerable distress to many patients who receive chemotherapy and to a lesser extent abdominal radiotherapy, and may lead to refusal of further treatment; prophylaxis of nausea and vomiting is therefore extremely important. Symptoms may be acute (occurring within 24 hours of treatment), delayed (first occurring more than 24 hours after treatment), or anticipatory (occurring prior to subsequent doses). Delayed and anticipatory symptoms are more difficult to control than acute symptoms and require different management. Patients vary in their susceptibility to drug-induced nausea and vomiting; those affected more often include women, patients under 50 years of age, anxious patients, and those who experience motion sickness. Susceptibility also increases with repeated exposure to the cytotoxic drug. Drugs may be divided according to their emetogenic potential and some examples are given below, but the symptoms vary according to the dose, to other drugs administered and to the individual’s susceptibility to emetogenic stimuli. Mildly emetogenic treatment— fluorouracil p. 961, etoposide p. 974, methotrexate p. 963 (less than 100 mg/m2, low dose in children), the vinca alkaloids, and abdominal radiotherapy. Moderately emetogenic treatment—the taxanes, doxorubicin hydrochloride p. 951, intermediate and low doses of cyclophosphamide p. 945, mitoxantrone p. 954, and high doses of methotrexate (0.1– 1.2 g/m2). Highly emetogenic treatment— cisplatin p. 973, dacarbazine p. 946, and high doses of cyclophosphamide. Prevention of acute symptoms For patients at low risk of emesis, pretreatment with dexamethasone p. 712 or lorazepam p. 355 may be used. For patients at high risk of emesis, a 5HT3-receptor antagonist, usually given by mouth in combination with dexamethasone and the neurokinin receptor antagonist aprepitant p. 453 is effective. Prevention of delayed symptoms For delayed symptoms associated with moderately emetogenic chemotherapy, a combination of dexamethasone and 5HT3-receptor antagonist is effective; for highly emetogenic chemotherapy, a combination of dexamethasone and aprepitant is effective. Rolapitant p. 454 and metoclopramide hydrochloride p. 452 are also licensed for delayed chemotherapy-induced nausea and vomiting. Prevention of anticipatory symptoms Good symptom control is the best way to prevent anticipatory symptoms. Lorazepam can be helpful for its amnesic, sedative, and anxiolytic effects. For information on the treatment of nausea and vomiting, see Nausea and labyrinth disorders p. 448. Treatment of cytotoxic-induced side-effects Anthracycline side-effects Anthracycline-induced cardiotoxicity The anthracycline cytotoxic drugs are associated with dose- related, cumulative, and potentially life-threatening cardiotoxic side-effects. Anthracycline extravasation Local guidelines for the management of extravasation should be followed or specialist advice sought. See further information on the prevention and management of extravasation injury. Chemotherapy-induced mucositis and myelosuppression Folinic acid p. 992 (given as calcium folinate) is used to counteract the folate-antagonist action of methotrexate p. 963 and thus speed recovery from methotrexate-induced mucositis or myelosuppression (‘folinic acid rescue’). Folinic acid is also used in the management of methotrexate overdose, together with other measures to maintain fluid and electrolyte balance, and to manage possible renal failure. Folinic acid does not counteract the antibacterial activity of folate antagonists such as trimethoprim p. 607. When folinic acid and fluorouracil p. 961 are used together in metastatic colorectal cancer the response-rate improves compared to that with fluorouracil alone. The calcium salt of levofolinic acid p. 993, a single isomer of folinic acid, is also used for rescue therapy following methotrexate administration, for cases of methotrexate overdose, and for use with fluorouracil for colorectal cancer. The dose of calcium levofolinate is generally half that of calcium folinate. The disodium salts of folinic acid and levofolinic acid are also used for rescue therapy following methotrexate therapy, and for use with fluorouracil for colorectal cancer. Urothelial toxicity Haemorrhagic cystitis is a common manifestation of urothelial toxicity which occurs with the oxazaphosphorines, cyclophosphamide p. 945 and ifosfamide p. 947; it is caused by the metabolite acrolein. Mesna p. 992 reacts specifically with this metabolite in the urinary tract, preventing toxicity. Mesna is used routinely (preferably by mouth) in patients receiving ifosfamide, and in patients receiving cyclophosphamide by the intravenous route at a high dose (e.g. more than 2 g) or in those who experienced urothelial toxicity when given cyclophosphamide previously. Anthracyclines and other cytotoxic antibiotics Drugs in this group are widely used. Many cytotoxic antibiotics act as radiomimetics and simultaneous use of radiotherapy should be avoided because it may markedly increased toxicity. Daunorubicin p. 950, doxorubicin hydrochloride p. 951, epirubicin hydrochloride p. 953 and idarubicin hydrochloride p. 953 are anthracycline antibiotics. Mitoxantrone p. 954 is an anthracycline derivative. Doxorubicin hydrochloride is available as both conventional and liposomal formulations. The different formulations vary in their licensed indications, pharmacokinetics, dosage and administration, and are not interchangeable. Conventional doxorubicin hydrochloride is used to treat the acute leukaemias, Hodgkin’s and non- Hodgkin’s lymphomas, paediatric malignancies, and some solid tumours including breast cancer. Epirubicin hydrochloride is structurally related to doxorubicin hydrochloride and can be used to treat breast cancer. Idarubicin hydrochloride has general properties similar to those of doxorubicin hydrochloride; it is mostly used in the treatment of haematological malignancies. Daunorubicin also has general properties similar to those of doxorubicin hydrochloride. Mitoxantrone is structurally related to doxorubicin hydrochloride. Pixantrone p. 954 is licensed as monotherapy for the treatment of refractory or multiply relapsed aggressive non- Hodgkin B-cell lymphomas, although the benefits of using it as a fifth-line or greater chemotherapy in refractory patients has not been established. Bleomycin p. 970 is given intravenously or intramuscularly to treat metastatic germ cell cancer and, in some regimens, non-Hodgkin’s lymphoma. Dactinomycin is principally used to treat paediatric cancers. Its side-effects are similar to those of doxorubicin, except that cardiac toxicity is not a problem. Mitomycin p. 970 can be given intravenously to treat gastro-intestinal, breast, non-small cell lung, and metastatic pancreatic cancers; and by bladder instillation for superficial bladder tumours. It causes delayed bone marrow toxicity. Vinca alkaloids The vinca alkaloids, vinblastine sulfate p. 979, vincristine sulfate p. 980, and vindesine sulfate p. 980, are used to treat a variety of cancers including leukaemias, lymphomas, and some solid tumours. Vinorelbine p. 981 is a semi-synthetic Immune system and malignant disease vinca alkaloid. See also, role of vinorelbine in the treatment of breast cancer. Antimetabolites Antimetabolites are incorporated into new nuclear material or combine irreversibly with cellular enzymes, preventing normal cellular division. Alkylating drugs Extensive experience is available with these drugs, which are among the most widely used in cancer chemotherapy. They act by damaging DNA, thus interfering with cell replication. Cyclophosphamide is used mainly in combination with other agents for treating a wide range of malignancies, including some leukaemias, lymphomas, and solid tumours. It is given by mouth or intravenously; it is inactive until metabolised by the liver. Ifosfamide is related to cyclophosphamide and is given intravenously. Melphalan p. 948 is licensed for the treatment of multiple myeloma, polycythaemia vera, childhood neuroblastoma, advanced ovarian adenocarcinoma, and advanced breast cancer. However, in practice, melphalan is rarely used for ovarian adenocarcinoma; it is no longer used for advanced breast cancer. Melphalan is also licensed for regional arterial perfusion in localised malignant melanoma of the extremities and localised soft-tissue sarcoma of the extremities. Lomustine p. 947 is a lipid-soluble nitrosourea and the drug is given at intervals of 4 to 6 weeks. Carmustine p. 943 has similar activity to lomustine; it is given to patients with multiple myeloma, non-Hodgkin’s lymphomas, Hodgkin’s disease, and brain tumours. Carmustine implants are licensed for intralesional use in adults for the treatment of recurrent glioblastoma multiforme as an adjunct to surgery. Carmustine implants are also licensed for high-grade malignant glioma as adjunctive treatment to surgery and radiotherapy. Estramustine phosphate p. 946 is a combination of an oestrogen and chlormethine used predominantly in prostate cancer. It is given by mouth and has both an antimitotic effect and (by reducing testosterone concentration) a hormonal effect. Mitobronitol is occasionally used to treat chronic myeloid leukaemia; it is available on a named-patient basis from specialist importing companies. ANTINEOPLASTIC DRUGS › ALKYLATING AGENTS
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Manufacturer advises inform patients to report any symptoms of depression or decreased interest.
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250 mg 3 times a day, review treatment if no
First-line fragment. Read the complete Indications and Dose section above.
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