New-Medicine-Report-Ondansetron

NHS Suffolk Drug & Therapeutics Committee New Medicine Report

This drug has been reviewed because it is a product that may be prescribed in primary care.

Medicine Ondansetron for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy

(NB: see also ondansetron for the prevention and treatment of post operative nausea and vomiting). Document status Reviewed January 2012 Suffolk D&TC Date of last revision 23rd January 2012 Traffic light decision Red – Hospital only Prescribers rating A real advance - The product is an important therapeutic innovation but has certain limitations

Mechanism of action Ondansetron is a potent, highly selective 5HT3 receptor- antagonist. Its precise mode of action in the control of nausea and vomiting is not known.

Chemotherapeutic agents and radiotherapy may cause release of 5HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5HT3 receptors. Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also cause a release of 5HT in the area postrema, located on the floor of the fourth ventricle, and this may also promote emesis through a central mechanism. Thus, the effect of ondansetron in the management of the nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is probably due to antagonism of 5HT3 receptors on neurons located both in the peripheral and central nervous system.

Ondansetron does not alter plasma prolactin concentrations. Medicine class Nausea and vertigo BNF 4.6 Indication Ondansetron is indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy and for the prevention and treatment of post-operative nausea and vomiting (PONV).

(Note: ondansetron is also used for a number of unlicensed indications including: drug-induced nausea and vomiting, gastroenteritis – Vomiting, hyperemesis gravidarum, Injection site pain, panic disorder, pruritus, schizophrenia, refractory; adjunct. Evidence for the unlicensed indications has not been

This is an NHS Suffolk document that has been adopted by the WSCCG.

considered. Dosage Chemotherapy and radiotherapy induced nausea and vomiting.

Adults: the emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The route of administration and dose of ondansetron should be flexible in the range of 8-32mg a day and selected as shown below.

Emetogenic Chemotherapy and Radiotherapy: Ondansetron can be given either by rectal, oral (tablets or liquid), intravenous or intramuscular administration.

For oral administration: 8mg 1-2 hours before treatment, followed by 8mg 12 hours later.

To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with ondansetron should be continued for up to 5 days after a course of treatment.

The recommended dose for oral administration is 8mg twice daily.

Highly Emetogenic Chemotherapy: For patients receiving highly emetogenic chemotherapy, e.g. high-dose cisplatin, ondansetron can be given either by oral, rectal, intravenous or intramuscular administration.

The recommended oral dose is 24mg taken together with oral dexamethasone sodium phosphate 12mg, 1 to 2 hours before treatment.

To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal treatment with ondansetron should be continued for up to 5 days after a course of treatment.

The recommended dose for oral administration is 8mg twice daily.

Paediatric Population:

CINV in children aged 6 months and adolescents

The dose for CINV can be calculated based on body surface area (BSA) or weight – see below. Weight-based dosing results in higher total daily doses compared to BSA-based dosing.

There are no data from controlled clinical trials on the use of ondansetron in the prevention of delayed or prolonged CINV. There are no data from controlled clinical trials on the use of ondansetron for radiotherapy- induced nausea and vomiting in children.

Dosing by BSA:

Ondansetron should be administered immediately before chemotherapy as a single intravenous dose of 5mg/m2. The intravenous dose must not exceed 8mg.

Oral dosing can commence twelve hours later and may be continued for up to 5 days (Table 1). The total daily dose must not exceed adult dose of 32mg. Table 1: BSA-based dosing for Chemotherapy - Children aged 6 months and adolescents

(a,b) (b) BSA Day 1 Days 2-6

2 2 < 0.6 m 5 mg/m i.v. plus 2 mg syrup every 2 mg syrup after 12 hrs 12 hrs

2 2 0 .6 m 5 mg/m i.v. plus 4 mg syrup or 4 mg syrup or tablet every 12 tablet after 12 hrs

hrs

a The intravenous dose must not exceed 8mg. b The total daily dose must not exceed adult dose of 32 mg

Dosing by bodyweight:

Weight-based dosing results in higher total daily doses compared to BSA-based dosing.

Ondansetron should be administered immediately before chemotherapy as a single intravenous dose of 0.15mg/kg. The intravenous dose must not exceed 8mg.

Two further intravenous doses may be given in 4 hourly intervals. The total daily dose must not exceed adult dose of 32mg.

Oral dosing can commence twelve hours later and may be continued for up to 5 days (Table 2).

Table 2: Weight-based dosing for Chemotherapy - Children aged 6 months and adolescents

(a,b) (b) Weight Day 1 Days 2-6

10 kg Up to 3 doses of 2 mg syrup 0.15 mg/kg every 4 every 12 hrs hrs

> 10 kg Up to 3 doses of 4 mg syrup 0.15 mg/kg every 4 or tablet hrs every 12 hrs

a The intravenous dose must not exceed 8mg.

b The total daily dose must not exceed adult dose of 32 mg.

Hepatic Impairment: clearance of ondansetron is significantly reduced and serum half-life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8mg should not be exceeded and therefore parenteral or oral administration is recommended. Treatment There are two other 5HT3 receptor antagonists alternatives granesetron and palonsetron

Other options include: Antihistamines, phenothiazines, domperidone, metoclopramide, neurokinin receptor antagonists (aprepitant and fosaprepitant), nabilone and hyosine.

See BNF 62 and relevant SPCs for licensed indications and doses. Place in therapy The management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy and for the prevention and treatment of post-operative nausea and vomiting (PONV) according to local guidelines and pathways. Future alternatives None known at present. Evidence for use Ondansetron is established in clinical use for the treatment and prophylaxis of adults and children with radiotherapy and chemotherapy induced nausea and vomiting. The key clinical trials were performed in the 80s and early 90s and have not been individually reviewed in this document.

A summary of the evidence, taken from DrugDex (a US drug information resource) is shown in appendix 1.

References available on request. NNT Not calculated Cautions / side Constipation, headache, flushing, injection site reactions, effects hiccups, hypotension, bradycardia, chest pain, arrhythmias, movement disorders, seizures.

On IV administration dizziness rarely, transient visual disturbances (very rarely transient blindness).

Suppositories may cause rectal irritation.

Cost within PbR In tariff tariff? Cost (prices from Preparation Price BNF 62) Ondansetron 4mg tablets x30 = £63.06 Ondansetron 8mg tablets x8 = £47.18 Ondansetron oral solution 4mg/5ml 50ml = £38.19

Ondansetron injection 2mg/ml 2ml amp £5.39 Ondansetron injection 2mg/ml 4ml amp £10.79 Zofran 4mg Melts x10 = £35.97 Zofran oral solution 4mg/5ml 50ml = £35.97 Zofran suppositories 16mg x1=£14.39

Comparative costs of Drug Cost other medicines Granesetron 1mg tablets x10 =£51.20 Granesetron injection 1mg/ml 1ml = £1.20 Granesetron injection 1mg/ml 3ml = £4.80 Palonsetron (Aloxi) 50mcg/ml 5ml=£55.89 Potential number of The majority of patients being treated for the patients & usage in management of nausea and vomiting induced by Suffolk PCT cytotoxic chemotherapy and radiotherapy would have ondansetron prescribed in secondary care.

Points for • Ondansetron is prescribed routinely, consideration prophylactically and post treatment for patients receiving chemo and radiotherapy at both IHT and the WSH. • With a move towards increased homecare delivery of drugs, the onus may fall to the GP to prescribe these ancillary drugs. Is the drug on the West Suffolk Hospital - yes WSH or IHT Ipswich Hospital - yes formularies? Decisions from other Cambridgeshire JPG - bodies Norfolk TAG - Red SMC/NICE – AWMSG – Comments sought from

Decision review date

This review has been based on the SPCs for Zofran (GSK) tablets and injection, BNF 62 and DrugDex. There are a variety of formulations, strengths and brands (including generics) of ondansetron. Please refer to the individual Summary of Product Characteristics available via www.medcines.org.uk/

References 1. Summary of Product Characteristics. Zofran 4 & 8mg tablets and melts, suppositories injection and syrup. GlaxoSmithKline UK. Date of revision of the texts 18/10/2011. Accessed 04/01/2012 via www.medicinescomplete.com 2. Martin J, editor. British National Formulary No 62. London: British Medical Association and The Royal Pharmaceutical Society of Great Britain; September 2011, p.257/8. 3. Klasco R, editor. DRUGDEX® System electronic version. Thomson Micromedex, Greenwood Village, Colorado, USA. Ondansetron, Drugdex evaluation. Accessed 30/12/2011 via http://www.thomsonhc.com.

Appendix 1 (from DrugDex) Evidence for the use of ondansetron in chemotherapy and radiotherapy induced nausea and vomiting.

Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy including cisplatin 50mg/m2 or greater. Ondansetron-treatment was significantly superior to historical placebo for the control of emesis during the 24 hour study period according to a randomized, double-blind, monotherapy study in 357 adult cancer patients receiving highly emetic cancer chemotherapy.

Patients were randomized to receive either placebo, ondansetron 24mg once daily, ondansetron 8mg twice daily, or ondansetron 32mg once daily. In an analysis of the primary endpoint, no emetic episodes and no required use of rescue antiemetic agents during the 24 hour study period occurred in 66% in the ondansetron 24mg group, 55% in the ondansetron 8mg group, and 55% in the ondansetron 32mg group. More than 90% of historical placebo control who received a cisplatin dose of 50mg/m2 or greater experienced vomiting. In a between-group analysis, no nausea was experienced during the 24 hour study period in 56% of patients in the ondansetron 24mg group compared with 36% in the ondansetron 8mg group (p=0.001) and 50% in the ondansetron 32mg group.

A second randomized, double-blind trial confirmed these results.

Chemotherapy-induced nausea and vomiting, Moderately emetogenic chemotherapy; Prophylaxis Complete or major control of emesis was similar with the administration of oral and orally disintegrating ondansetron in 427 adult cancer patients receiving a single intravenous dose of cyclophosphamide (500mg/m2 ) or more. In double-blind, double-dummy fashion, patients were randomized to receive oral ondansetron 8mg (n=212) or the orally disintegrating tablet 8mg (n=215) 1 to 2 hours prior to chemotherapy, 8 hours later, and twice daily for the next 2 days. On the worst day, complete or major control was achieved in 80% and 78% of patients receiving oral or orally disintegrating tablets, respectively. Overall antiemetic control and antinausea efficacy were similar between treatment groups. Adverse effects were also similar; headaches and constipation occurred with similar frequency with both dosage forms.

In a double-blind study (n=336), oral ondansetron tablets 8mg administered twice daily was as effective as 3 times daily in preventing nausea and vomiting in patients receiving cyclophosphamide-based chemotherapy containing either methotrexate or doxorubicin. Patients were randomized to the 3 times daily or twice daily regimen and then evaluated for antiemetic response over 3 days. Patients in the twice daily treatment group had a 71% major response (0 to 2 emetic episodes) as compared to the 3 times daily treatment group which had a 68% major response. The nausea score, as evaluated by a visual analog scale (0=no nausea, 100=nausea as bad as it can be), was identical in both groups (score, 6).

Radiation-induced nausea and vomiting; Prophylaxis In a double-blind trial (n=135), ondansetron was significantly more effective in preventing vomiting (complete control of emesis defined as no emetic episodes) compared with prochlorperazine in patients receiving a 1 to 4 week course of fractionated radiotherapy (180 centigray/dose) to the abdomen. Patients received an ondansetron 8mg tablet or prochlorperazine 10mg tablet orally 1 to 2 hours before the first dose of radiotherapy followed by 2 additional doses (total of 3 doses/day). Additionally, treatment was continued 3 times daily on each day of radiotherapy.

In a double-blind trial (n=105), ondansetron was significantly more effective in preventing vomiting (complete control of emesis defined as no emetic episodes) compared with metoclopramide in patients receiving a single 800 to 1000 centigray dose of radiotherapy to the abdomen. Patients received an ondansetron 8mg tablet or metoclopramide 10 mg tablet orally 1 to 2 hours before radiotherapy followed by the same dose in the late afternoon and before bedtime (only the bedtime dose was given if a patient received radiotherapy in the afternoon). Additionally, treatment was continued 3 times daily for 3 days. Ondansetron was significantly more effective in preventing vomiting compared with placebo in patients receiving total body irradiation in a randomized, double-blind trial (n=20). Patients received an ondansetron 8mg tablet or placebo tablet 1.5 hours before each fraction of radiotherapy for 4 days. Total body irradiation was given as 120 centigray (cGy)/fraction for 3 fractions/day for 3 days and then 120 cGy/fraction for 2 fractions/day for 1 day (total of 1320 cGy).

Chemotherapy-induced nausea and vomiting, Initial and repeat courses of highly emetogenic chemotherapy; Prophylaxis Ondansetron oral tablets are indicated for the prevention of nausea and vomiting associated with highly emetogenic chemotherapy, including cisplatin doses of 50mg/m2 or greater.

Intravenous ondansetron is approved for prevention of nausea and vomiting associated with initial and repeat courses of emetogenic chemotherapy, including high-dose cisplatin.

Several modes of intravenous ondansetron have been used (intermittent bolus, single bolus, and continuous infusion) and all appear to be effective.

Oral ondansetron FOLLOWING intravenous administration appears to be effective.

A total daily dose of ondansetron 24mg and 32mg was shown to have similar efficacy in the prevention of nausea and vomiting in male patients with non-small cell lung cancer receiving chemotherapy. Patients (n=100) who had already received 3 cycles of chemotherapy were randomized to receive ondansetron 8mg every 8 hours (Group A) or ondansetron 8mg every 6 hours (Group B) for 4 days. Ondansetron was administered intravenously in combination with dexamethasone 8mg on day 1 before the start of chemotherapy, followed by oral administration in combination with dexamethasone 4mg for the next 3 days. All chemotherapeutic regimens consisted of cisplatin 100mg/m 2 of body surface area plus vinblastine, with or without mitomycin C or etoposide. The rate of complete antiemetic response (no emetic episodes) during the first 24 hours was 28% in group A and 34% in group B. The failure rates (greater than 5 emetic episodes or requiring rescue anti-emetic therapy) were 14% and 10%, respectively. The differences were not statistically significant. There was also no difference in response and failure rates on each of the 3 days after chemotherapy. However, patients in group B experienced significantly more constipation and headache as compared to group A (p less than 0.05).

Intravenous ondansetron administered intermittently in doses of 0.1 to 0.48 mg/kg every 2 to 8 hours (total of 3 to 6 doses) has been effective in controlling acute emesis following chemotherapeutic regimens, including high-dose cisplatin therapy (100 to 120mg/m2).

Complete plus major control of emesis (0 to 2 emetic episodes) has been observed in 50% to 100% of patients treated with these doses. Based upon available data, the optimal intermittent dose appears to be 0.15 to 0.18 mg/kg every 2 to 8 hours for 3 doses

Increasing the dose above 0.18mg/kg does not appear to enhance the efficacy of ondansetron but may increase the incidence of adverse effects. No consistent relationship between plasma levels and efficacy has been observed; however, in some European studies utilizing intermittent dosing, the majority of vomiting episodes occurred when plasma levels decreased to less than 30 nanograms/milliliter.

Intravenous ondansetron is effective in preventing cisplatin-induced nausea and vomiting. Ondansetron also delays the onset of emesis as compared to placebo. In this placebo- controlled, double-blind study, antiemetic efficacy of ondansetron was evaluated in 28 patients receiving cisplatin for a variety of malignancies. Cisplatin was given alone or in combination with other chemotherapeutic agents in doses ranging from 50 to 120mg/m2. Ondansetron 0.15mg/kg intravenously or placebo (normal saline) were given 30 minutes before initiation of the cisplatin infusion; placebo or ondansetron 0.15 milligram/kilogram intravenously were repeated at 4 and 8 hours following the initial dose (total of 3 doses at 4 hour intervals). During the 24-hour study period, ondansetron was superior to placebo in preventing cisplatin-induced nausea and vomiting. Antiemetic rescue therapy was required in 12 of the 14 placebo patients, but in none of 14 treated with ondansetron. The median number of vomiting episodes in 24 hours was reduced significantly with ondansetron as compared to placebo (1.5 versus 5.5 episodes). Ondansetron also significantly delayed onset of emesis; the median time to onset of emesis was 2.8 hours with placebo and 11.6 hours with ondansetron. In addition, the mean number of regurgitations or dry heaves per episode was significantly less with ondansetron (1.17) as compared to placebo.

Ondansetron was able to control acute emesis in about 72% of chemotherapy cycles in women treated with cisplatin chemotherapy protocols. In this open study, 21 patients affected by ovarian carcinoma were being treated with cisplatin chemotherapy protocols. There were 10 patients under first line adjuvant chemotherapy and 11 patients in relapse having already undergone previous antineoplastic treatments. The ondansetron regimens were based on the total quantity of cisplatin administered. The following regimens were used: Less than or equal to 100 milligrams (mg) of cisplatin - ondansetron, 8 mg IV before the scheduled chemotherapy course, followed by the same dose after completion of chemotherapy; Greater than 100mg cisplatin - ondansetron 16mg IV, followed by 8mg IV after completion of chemotherapy. Both groups received 8mg of ondansetron orally, 8 hours after completion of IV infusion. For the prevention of delayed (longer than 24 hours) nausea and vomiting, all patients received oral ondansetron therapy (8mg three times daily) days 2 through 5. A satisfactory control of acute emesis (0 to 2 episodes) occurred in 45/63 (71.4%) cycles; a minor response (3 to 5 episodes) occurred in 12/63 cycles (19%); the response was classified as a failure (more than 5 emetic episodes) in 6/63 cycles (9.5%). Nausea protection was complete in 24/63 cycles (38.1%), nausea was mild in 12 cycles (19%), bearable in 6 cycles (9.5%), severe in 21 cycles (33.3%). Adverse reactions were minor.

An open, non-comparative study demonstrated that a combination of ondansetron and dexamethasone achieved complete protection against acute emesis in about 62% of patients treated with cisplatin. This trial had 22 cancer patients receiving cisplatin chemotherapy at doses greater than 100mg/m2. Antiemetic therapy consisted of ondansetron (8 mg IV), 30 minutes before chemotherapy and 4 hours and 8 hours after the chemotherapy) and dexamethasone (20mg IV, 45 minutes prior to the chemotherapy). Complete protection from vomiting was obtained in 68.2% of patients, while major protection (1 to 2 vomiting episodes) was achieved in 13.6% of cases. Fifty-five percent of the patients did not have nausea, 45.4% had neither nausea or vomiting; only 3 patients reported adverse effects (headache and constipation).

The antiemetic efficacy of ondansetron at 10 dosage levels, ranging from 0.04 to 0.35 mg/kg IV, was evaluated in patients treated with cisplatin alone, cyclophosphamide alone, mitomycin plus vinblastine, cyclophosphamide plus doxorubicin plus vincristine, lomustine plus methotrexate, or vinblastine alone, primarily for bronchogenic carcinoma. Ondansetron was administered as a 15-minute infusion every 2 hours for a total of 3 doses. The first dose was given 30 minutes prior to chemotherapy. Significant antiemetic effects were observed in patients receiving all regimens, and throughout all dose levels administered. No dose-related toxicities were seen, with the most common adverse effects being mild sedation, dizziness, headache, dry mouth, and transient elevations in transaminases. No patient experienced akathisia or acute dystonic reactions. The authors suggest that ondansetron can be given safely in doses up to 0.35 milligram/kg in patients receiving chemotherapy.

Control of acute (within 24 hours) vomiting was achieved in 74% of the cisplatin cycles and 82% of the cycles without cisplatin, using ondansetron in 47 patients receiving a total of 269 cycles of chemotherapy for breast or genital neoplasms. Patients were subdivided into two groups: women subjected to chemotherapy without cisplatin (30 patients; 186 cycles of chemotherapy) and those with high doses of cisplatin alone or combined with other chemotherapeutic agents (17 patients; 83 cycles of chemotherapy). The dose of ondansetron initially used in the group treated with cisplatin was 8mg IV, 30 minutes before chemotherapy, followed by two oral administrations at 12 and 24 hours. In the cisplatin-treated group, ondansetron 16mg IV was administered before chemotherapy, in combination with 1 gram of dexamethasone IV, followed by oral administration as for the previous group. The major adverse effects with ondansetron were headache (42%) and constipation (49%); no extrapyramidal symptoms were observed.

Continuous 24 hour IV infusions of ondansetron have also been effective in preventing cisplatin-induced emesis. The most effective regimen appears to be an initial loading dose of 8mg IV (over 15 minutes) followed by a continuous infusion at a rate of 1mg/hour for 24 hours (total dose, 32 mg/24 hours). It has been suggested that this dosing schedule is as effective as an intermittent regimen employing 0.18mg/kilogram regimen every 2 to 4 hours for 3 doses. Higher dose regimens (eg, 10 to 12mg initially followed by 24 hours infusions of 2 to 4 mg/hour) have not been associated with greater antiemetic efficacy. No consistent relationship between plasma levels and efficacy has been observed with continuous infusions.

The efficacy of the ondansetron 8mg dose is similar to the 24mg dose, when combined with dexamethasone, for the prevention of acute vomiting in patients treated with cisplatin. In this trial, patients received either ondansetron 8mg IV plus dexamethasone 20mg IV or ondansetron 24mg IV plus dexamethasone 20mg IV, given as a single dose prior to infusion of high-dose (greater than 80 mg/m2 cisplatin. All patients received ondansetron 8 mg orally twice daily on days 2 through 5. Complete prophylaxis of acute nausea was demonstrated in 61% and 65% of patients, respectively. Prophylaxis of acute vomiting was achieved in 68% and 70% of patients, respectively. Similar results were demonstrated during the second cycle of chemotherapy, as well. As both dosing regimens demonstrated similar effectiveness, the authors concluded that ondansetron 8mg IV plus dexamethasone 20mg IV, followed by oral ondansetron 8mg twice daily, should be used for the prevention of cisplatin-induced nausea and vomiting.

Single dose IV ondansetron therapy was shown to be as effective as intermittent IV dosing. This trial compared single IV doses of ondansetron of either 8 or 32mg to multiple doses of 0.15mg/kg for 3 doses (conventional dosing) during cisplatin chemotherapy. Single doses were administered prior to chemotherapy and conventional doses were given in the usual dosing schedule. The antiemetic efficacy of the 32-mg dose was at least equal in efficacy observed with the conventional dosing regimen. The patients that received 8 mg had mixed results. In one study, 618 patients were randomized into 3 groups in a multi-center, double blind, parallel group trial. Patients received either ondansetron 32mg as a single IV dose, 8mg as a single IV dose, or 0.15 mg/kg for 3 doses, for the prevention of cisplatin-induced nausea and vomiting. Patients who received the 32 mg IV dose had significantly less nausea and vomiting than patients in the 0.15 mg/kg for 3 doses group or the group that received 8 mg as a single IV dose. There were no significant differences between groups for adverse effects noted.

Single-dose intravenous (IV) ondansetron therapy followed by oral ondansetron was only effective in preventing delayed vomiting in 62% of patients. In this multicenter study, ondansetron was combined with dexamethasone (DXM) for the prevention of nausea and vomiting in adult patients receiving high-dose cisplatin (greater than 50 milligrams/square meter) therapy. The following dosage regimens were used: Ondansetron - 8 milligrams (mg) IV followed by ondansetron 8 mg orally twice daily for 6 days; DXM - 20 mg IV combined with the initial ondansetron dose then DXM 8 mg intramuscularly twice daily on days 2 and 3, then 4 mg twice daily on day 4. Complete protection from delayed vomiting and nausea was achieved in 62% and 43.7% of patients, respectively.

Oral ondansetron has been proven to be safe and effective in the prevention of nausea and vomiting associated with emetogenic chemotherapy. The recommended adult oral dose of ondansetron is 8mg administered twice daily. The first dose should be administered 30 minutes prior to chemotherapy then repeated 8 hours later. Oral ondansetron therapy should be continued for 1 to 2 days after the completion of chemotherapy. The efficacy rate of oral ondansetron in clinical trials for patients receiving non-cisplatin based chemotherapy regimens range from 60 to 90%; Clinicals trials have proven that the efficacy of ondansetron dosed 8 mg twice daily is equivalent to 8 mg 3 times daily in patients receiving cyclophosphamide-based chemotherapy containing combinations of either doxorubicin, epirubicin, or methotrexate. Clinical trials have found that oral ondansetron is effective in the prevention of emesis following non-cisplatin based chemotherapy. In two studies, ondansetron was administered intravenously, orally, or a combination of the two, in doses of 8mg every 5, 8, or 10 hours. Greater than 80% of patients in both studies had a complete or major antiemetic response (0 to 2 emetic episodes) over the 1 to 5 days following treatment. In a third study, oral ondansetron 8mg twice daily was compared to placebo in 67 patients receiving cyclophosphamide-based chemotherapy containing doxorubicin. Patients receiving ondansetron had a 79% complete or major response (0 to 2 emetic episodes) over the 3 day study period.

In a dose-ranging study, oral ondansetron administered twice daily was as effective as 8mg 3 times daily in preventing nausea and vomiting in patients receiving cyclophosphamide-based chemotherapy containing either methotrexate or doxorubicin. Patients (n=336) were randomized to the 3 times daily or twice daily regimen and then evaluated for antiemetic response over 3 days. Patients in the twice daily treatment group had a 71% major response (0 to 2 emetic episodes) as compared to the 3 times daily treatment group which had a 68% major response. The nausea score, as evaluated by a visual analog scale (0= no nausea, 100=nausea as bad as it gets), was identical in both groups (ie, score = 6).

Additional study is needed to determine if ondansetron should be recommended, over conventional therapy, for the treatment of cisplatin-induced DELAYED EMESIS. Type 3, serotonin-receptor antagonists, including ondansetron,are generally not effective for the prevention of cisplatin-induced delayed emesis; although mixed results do exist. Treatment failure may be attributed to a different mechanism of action for delayed emesis; however, conventional therapy is recommended for the treatment of delayed emesis. A more recent study has demonstrated favorable results for ondansetron in the treatment of cisplatin- induced delayed emesis. Unfortunately, the efficacy may have been related to the effects of ondansetron on moderately emetogenic chemotherapy that was used in combination with cisplatin over a multiple number of days.

Oral ondansetron was effective in dacarbazine-induced emesis. In this open, non- comparative trial, the antiemetic efficacy of ondansetron was assessed in 19 chemotherapy- naive patients receiving chemotherapy, including dacarbazine (500mg/m2/day) day 1, every 4 weeks). At the first course of therapy, 18 patients received ondansetron 8mg orally 1 hour prior to chemotherapy and then 6 and 12 hours later; ondansetron 8mg orally was administered three times daily on days 2 and 3. Complete and major control (1 to 2 emetic episodes) of acute emesis (within 24 hours of chemotherapy) occurred in 8 (44.4%) and 7 (38.8%) patients, respectively; nausea was absent in 8 (44.4%), or mild in 6 patients (33.3%). Few adverse effects were reported (constipation, 4 cases; headache, 4 cases).

Oral ondansetron has been shown to be effective in controlling emesis in patients with severe (more than 15 emetic episodes) post-chemotherapy emesis, refractory to prior combination antiemetic therapy. In this open, non-comparative study, the dosage of oral ondansetron was 8 milligrams (mg) three times daily for 5 days; the first dose given 1 hour prior to chemotherapy. Not all patients in this trial were treated with cisplatin. Complete or major protection (1 to 2 emetic episodes) from emesis was achieved in 87.5% of the cases (complete: 37.5%; major protection: 50%). No adverse effects were observed.

Oral ondansetron (8 or 12mg three times daily for 5 days) following a 24 hour infusion has been effective in maintaining antiemetic effects in patients receiving cisplatin. One clinical trial demonstrated that oral ondansetron (8 mg) following an intravenous dose of ondansetron was effective in patients receiving moderate dose of cisplatin- containing regimens. Some investigators indicate that oral ondansetron therapy alone should be effective in most patients. However, some investigators recommend only intravenous therapy (loading dose and continuous 24-hour infusion) in patients receiving high-dose cisplatin.

Combination antiemetic therapy with ondansetron and dexamethasone was effective at preventing acute and delayed emesis in patients receiving emetogenic chemotherapy. In this open, non-comparative study, the antiemetic efficacy of ondansetron and dexamethasone was evaluated in 40 chemotherapy naive patients receiving cisplatin, dacarbazine or other emetogenic drugs. The antiemetic dosage was as follows: ondansetron 8mg IV in combination with dexamethasone 8mg IV before chemotherapy. Oral ondansetron 8mg was subsequently given in the evening of day 1 and then every 12 hours on days 2, 3, and 4. During the first cycle, complete control of acute emesis was achieved in 88% of cases and no delayed emesis was recorded in 76%. Acute and delayed nausea were absent in 78% and 69% of cases, respectively. During the second, third and fourth cycles, complete control of acute emesis was achieved in 92%, 80% and 86% of cases, respectively; no delayed emesis occurred in 71%, 82% and 82% of cases, respectively.

According to the results of an open, non-comparative trail, oral ondansetron, in combination with IV dexamethasone, was an effective in the prevention of acute emesis as well as delayed emesis. This antiemetic regimen was evaluated in 58 chemotherapy-naive patients with gynecological cancer, receiving cisplatin based chemotherapy (40 to 80 mg/m2. The following antiemetic dosage regimen was used: Day 0, oral ondansetron (8mg 3 times daily) in combination with intravenous dexamethasone (16 mg); Days 1 through 7, oral ondansetron (8mg twice daily). In cycle 1, complete or major control (0 to 2 emetic episodes) of emesis was achieved in 94.6% of the patients in the acute phase (day 0) and in 89.2% in the delayed phase (days 1 through 7). In the subgroup of patients receiving cisplatin at a dose greater than 75 mg/m2, the effect on acute and delayed emesis decreased with subsequent courses. Reversible adverse reactions were observed in 8.9% of the cases (mainly headache and constipation).

In several studies, the addition of dexamethasone was effective in improving emetic control in patients unresponsive to ondansetron alone

For some non-cisplatin containing regimens (eg, cyclophosphamide, methotrexate, and 5- fluorouracil), ONDANSETRON 8 mg followed by METOCLOPRAMIDE 10 mg every 8 hours is as effective (complete and major response, 80%) as ondansetron alone for several days (complete and major response, 77.8%). However, for regimens containing the combination of cyclophosphamide, epirubicin, and 5-fluorouracil, ondansetron 8 mg prior to chemotherapy then repeated every 8 hours for 3 days is superior (complete and major response, 80%) to a single dose of ondansetron followed by metoclopramide for 3 days (complete and major response, 44%). Unfortunately, neither antiemetic regimen is effective in treating delayed nausea and vomiting.

Ondansetron, combined with metoclopramide, was effective in preventing emesis (ie, complete plus major protection) in about 75% of patients receiving high-dose cisplatin. In this open, non- comparative study, the efficacy of ondansetron plus metoclopramide was assessed in 40 chemotherapy naive patients. At the first cycle of chemotherapy, on day 1, patients received ondansetron (16 mg IV plus metoclopramide (0.5 mg/kg IV) before cisplatin administration; then ondansetron, 8mg orally twice daily and metoclopramide, 0.5mg/kg IM three times daily were given for 4 days. At the second cycle, all patients received the same antiemetic treatment as above plus methylprednisolone, 125 mg IV on day 1 and then intravenously once a day for 4 days. At cycle 1, complete protection against acute emesis was achieved in 55% of cases; major protection (1 to 2 emetic episodes) in 30%; minor protection (3 to 5 emetic episodes) in 10%; failure accounted for 5% of cases. At cycle 2, complete protection from vomiting was achieved in 47% of cases, while major protection was achieved in 30% of treated patients. After the first cycle, complete protection from emesis was observed in 23%, major protection in 33%, minor protection in 25% of the patients. Type and frequency of side effects were in the range reported in other studies with ondansetron.

Pediatric: In a prospective, randomized, double-blind study, a single high dose of IV ondansetron was as effective as multiple standard doses in preventing chemotherapy-induced emesis in 31 newly diagnosed pediatric oncology patients. Using an emesis scale (1: no nausea or emesis; 2: nausea, but able to eat; 3: nausea, unable to eat; 4: emesis), 81% and 80% of patients receiving single- and multiple-dose treatment, respectively, chose ratings of 1 or 2 during the 48 hours following chemotherapy. Antiemetic treatment consisted of a single dose of ondansetron (0.6 milligrams per kilogram (mg/kg))given intravenously (IV) prior to chemotherapy (n=16) or 0.15 mg/kg IV every 4 hours for 4 doses (n=15). In chemotherapy-naive children receiving highly emetogenic chemotherapy ondansetron achieved complete (no emesis) or major control (1 to 2 emetic episodes) in 71% to 72% of patients. No or mild nausea was reported in 86 to 90% of patients. An initial loading dose of 5 or 10 milligrams/square meter (mg/m(2)) followed by 5 mg/m(2) eight and 16 hours after the initial dose was used to treat acute emesis. No statistical differences were observed between the 2 different loading doses. Patients subsequently received oral ondansetron 4 mg (less than 1 m(2) body surface area (BSA)) or 8 mg (greater than or equal to 1 m(2) BSA) 3 times daily. Ondansetron was not effective in preventing cisplatin-induced DELAYED emesis [100].

Oral and intravenous ondansetron when used in combination with dexamethasone were shown to be equally effective as antiemetic therapy in the prophylaxis of nausea and vomiting induced by moderately or highly emetogenic chemotherapy in pediatric and adolescent patients. In this double-blinded study, patients between 1 and 17 years old (mean age, 8 years) were randomized to 1 of 2 treatment groups. Prior to chemotherapy, Group 1 (n=212) received an intravenous loading dose of ondansetron 5 milligrams per square meter body surface area and Group 2 (n=216) received a loading dose of 8 mg ondansetron syrup. All patients received oral dexamethasone 2 to 4 mg based on the patient's body weight. Approximately 6 to 8 hours after receiving the chemotherapy, all patients received oral ondansetron 4 mg syrup plus oral dexamethasone 2 to 8 mg and continued each day throughout the chemotherapy treatment for a maximum of 8 days. In addition, all patients received ondansetron 4 mg orally twice a day for 2 days after chemotherapy. No significant differences were found in the rates of complete control of emesis (range, 62% to 81%) or in the rates of complete or major emetic control (range, 82% to 91%) at any point during the study between the two groups. The incidence of adverse events was also similar [68].

Chemotherapy-induced nausea and vomiting, Initial and repeat courses of moderately emetogenic chemotherapy; Prophylaxis For some non-cisplatin containing regimens (eg, cyclophosphamide, methotrexate, and 5- fluorouracil), ONDANSETRON 8mg followed by METOCLOPRAMIDE 10mg every 8 hours is as effective (complete and major response, 80%) as ondansetron alone for several days (complete and major response, 77.8%). However, for regimens containing the combination of cyclophosphamide, epirubicin, and 5-fluorouracil, ondansetron 8 milligrams prior to chemotherapy then repeated every 8 hours for 3 days is superior (complete and major response, 80%) to a single dose of ondansetron followed by metoclopramide for 3 days (complete and major response, 44%). Unfortunately, neither antiemetic regimen is effective in treating delayed nausea and vomiting.

According to a comprehensive meta-analysis, 5-HT(3) antagonists including ondansetron are more effective than metoclopramide in the treatment of acute chemotherapy-induced vomiting. The addition of dexamethasone to a 5-HT(3) antagonist regimen augments its efficacy. Major advantages of the 5-HT(3) antagonists, over conventional antiemetics (eg, high-dose metoclopramide), include fewer side effects and a simplified dosing regimen.

A continuous IV infusion of ondansetron has been used to effectively to control nausea and vomiting after high-dose melphalan in patients with multiple myeloma. Ondansetron was administered prior to melphalan as a loading dose of 8 milligrams (infused over 15 minutes), followed by a continuous IV infusion of 1 milligram/hour (mg/hr) for 48 hours. Oral therapy was then initiated in a dose of 8 mg every 6 hours (from days 3 to 7). Administration of larger doses during the first 24 hours (84 milligrams total) did not enhance antiemetic efficacy in this study.

Ondansetron was evaluated in 15 patients receiving non-cisplatin chemotherapy regimens. All patients had been previously unresponsive to first-line antiemetic therapy (domperidone, dexamethasone, domperidone plus dexamethasone, metoclopramide plus dexamethasone). Ondansetron 4mg was administered concomitantly by the intravenous and oral routes immediately prior to chemotherapy. The oral dose was repeated at 5 and 10 hours following chemotherapy. Thirty-one courses of ondansetron were given, with only 1 patient experiencing nausea and vomiting (chemotherapeutic regimen in this patient not specified). Nausea, retching, or vomiting were not observed in the other 30 patients.

The antiemetic efficacy of ondansetron at 10 dosage levels, ranging from 0.04 to 0.35mg/kg IV, was evaluated in patients treated with cisplatin alone, cyclophosphamide alone, mitomycin plus vinblastine, cyclophosphamide plus doxorubicin plus vincristine, lomustine plus methotrexate, or vinblastine alone, primarily for bronchogenic carcinoma. Ondansetron was administered as a 15 minute infusion every 2 hours for a total of 3 doses. The first dose was given 30 minutes prior to chemotherapy. Significant antiemetic effects were observed in patients receiving all regimens, and throughout all dose levels administered. No dose-related toxicities were seen, with the most common adverse effects being mild sedation, dizziness, headache, dry mouth, and transient elevations in transaminases. No patient experienced akathisia or acute dystonic reactions. The authors suggest that ondansetron can be given safely in doses up to 0.35mg/kg in patients receiving chemotherapy.

Control of acute (within 24 hours) vomiting was achieved in 74% of the cisplatin cycles and 82% of the cycles without cisplatin, using ondansetron in 47 patients receiving a total of 269 cycles of chemotherapy for breast or genital neoplasms. Patients were subdivided into two groups: women subjected to chemotherapy without cisplatin (30 patients; 186 cycles of chemotherapy) and those with high doses of cisplatin alone or combined with other chemotherapeutic agents (17 patients; 83 cycles of chemotherapy). The dose of ondansetron initially used in the group treated with cisplatin was 8mg IV 30 minutes before chemotherapy, followed by two oral administrations at 12 and 24 hours. In the cisplatin-treated group, ondansetron 16mg IV was administered before chemotherapy, in combination with 1 gram of dexamethasone IV, followed by oral administration as for the previous group. The major adverse effects with ondansetron were headache (42%) and constipation (49%); no extrapyramidal symptoms were observed.

Clinicals trials have demonstrated that the efficacy of oral ondansetron dosed 8mg twice daily is equivalent to 8mg 3 times daily, in patients receiving cyclophosphamide-based chemotherapy regimens containing combinations of either doxorubicin, epirubicin, or methotrexat. The efficacy rate of oral ondansetron in clinical trials for patients receiving non- cisplatin based chemotherapy regimens range from 60% to 90%. In low to moderate emetogenic chemotherapy regimens, conventional anti-emetics are recommended.

The efficacy rate of oral ondansetron in clinical trials for patients receiving non-cisplatin based chemotherapy regimens range from 60 to 90%. Clinical trials have proven that the efficacy of ondansetron dosed 8mg twice daily is equivalent to 8mg 3 times daily in patients receiving cyclophosphamide-based chemotherapy containing combinations of either doxorubicin, epirubicin, or methotrexate.

Complete or major control of emesis was similar with the administration of oral and orally disintegrating ondansetron in 427 adult cancer patients receiving a single intravenous dose of cyclophosphamide (500 mg/m2 or more). In double-blind, double-dummy fashion, patients were randomized to receive oral ondansetron 8mg (n=212) or the orally disintegrating tablet 8 mg (n=215) 1 to 2 hours prior to chemotherapy, 8 hours later, and twice daily for the next 2 days. On the worst day, complete or major control was achieved in 80% and 78% of patients receiving oral or orally disintegrating tablets, respectively. Overall antiemetic control and antinausea efficacy were similar between treatment groups. Adverse effects were also similar; headaches and constipation occurred with similar frequency with both dosage forms.

In a phase II trial, a single oral dose of ondansetron used in combination with intravenous dexamethasone was shown to be effective in preventing carboplatin-induced nausea and vomiting in women with pelvic malignancies. Oral ondansetron 16 milligrams (mg) and intravenous dexamethasone 20 mg were administered to 27 patients 30 minutes prior to initiation of chemotherapy. The median age of the patient was reported to be 62 years and the most common diagnoses were ovarian and endometrial cancer. The response rate for complete control of emesis was 93% and the incidence of nausea was 7%. No delayed emesis was reported. Ondansetron plus dexamethasone was found to be significantly (p less than 0.001) more effective than metoclopramide plus dexamethasone, in the prevention of carboplatin-induced nausea and vomiting. Patients in the ondansetron / dexamethasone group received ondansetron 8mg orally twice daily on days 2 and 3. The metoclopramide group received oral metoclopramide 20 mg three times daily, on days 2 and 3.

Oral ondansetron in combination with oral dexamethasone may be beneficial in preventing delayed emesis associated with cyclophosphamide. In a retrospective study, 14 patients with lupus who had previously failed a combination antiemetic regimen of thiethylperazine, diphenhydramine, and lorazepam were given ondansetron 8mg every 4 hours for 3 doses and dexamethasone 10mg (1 dose) starting 4 hours after cyclophosphamide (0.75 to 1 gram per square meter). None of the patients experienced emesis. In addition, therapy was well- tolerated and none of the patients reported headache.

Oral ondansetron was shown to control acute emesis in 94.5% of patients receiving cyclophosphamide chemotherapy. In this open, non-comparative study, 55 patients were treated with ondansetron for the prevention of nausea and vomiting induced by cyclophosphamide IV (more than 600 milligrams/square meter/day (mg/m(2)/day)). During their first treatment course, patients received ondansetron 8 mg orally three times daily for a minimum of 3 days to a maximum of 5 days. At day 1, complete and major control (1 to 2 emetic episodes) of acute emesis was observed in 94.5% of the patients while in 83.3% of cases acute nausea was graded as absent or mild. Complete and major control of emesis improved on subsequent study days; adverse effects were mild

In a large Canadian cancer facility, ondansetron use altered patient management of chemotherapy-related nausea and vomiting and resulted in cost savings associated with those changes. A retrospective analysis comparing costs (drug, personnel time, supplies, and "hotel") per patient per month before and after ondansetron introduction identified a 374 dollar reduction largely related to avoidance of facility bed costs. The efficacy of ondansetron allowed larger doses of chemotherapy to be administered over shorter time periods in outpatient settings. In addition, ondansetron use was associated with a decrease in benzodiazepine premedication and an earlier discharge following completed chemotherapy. A subsequent change to oral ondansetron was successfully instituted with expected additional cost savings.

Pediatric: Intravenous (IV) ONDANSETRON was safe and effective in reducing the incidence and severity of vomiting in pediatric patients undergoing intrathecal chemotherapy, based on a randomized, placebo-controlled, crossover study (n=26). Enrollees were children and adolescents (aged 2 to 17 years, mean 6 years) who were newly diagnosed with acute lymphoid or nonlymphoid leukemia. Intrathecal chemotherapy consisted of methotrexate or the combination of methotrexate, hydrocortisone, and cytarabine. Most of the cohort received sedation and analgesia with midazolam and ketamine before chemotherapy. Subjects were randomized to 1 of 3 interventions: placebo, ondansetron at 0.15 milligram/kilogram (mg/kg) (low dose), or ondansetron at 0.45 mg/kg (high dose); each was given as a 15-minute IV infusion 30 minutes before the lumbar puncture. Study protocols were administered in random order for up to 6 intrathecal treatments, with each patient acting as his/her control. Overall 23 of 26 patients (88.5%) had post-procedure vomiting on at least 1 occasion. There was at least 1 vomiting episode after 32 (62.7%) placebo treatments. One or more vomiting episodes occurred after 13 (27.7%) low-dose ondansetron and after 7 (14.6%) high-dose ondansetron treatments. Chemotherapy sessions which were preceded by ondansetron of any dose were had significantly fewer number of vomiting episodes than placebo (p less than 0.005). Difference between the 2 doses of ondansetron treatment was not significant. For placebo treatment, the relative risk (RR) of vomiting was twice as great as the risk with low-dose ondansetron treatment (RR=2.3) and 4 times higher than the risk with high- dose therapy (RR=4.3). Almost all vomiting episodes considered severe (4 or more episodes) were associated with placebo use (13 of 15; 86.7%).

In a prospective, randomized, double-blind study, a single high dose of intravenous (IV) ondansetron was as effective as multiple standard doses in preventing chemotherapy- induced emesis in 31 newly diagnosed pediatric oncology patients. Using an emesis scale (1: no nausea or emesis; 2: nausea, but able to eat; 3: nausea, unable to eat; 4: emesis), 81% and 80% of patients receiving single- and multiple-dose treatment, respectively, chose ratings of 1 or 2 during the 48 hours following chemotherapy. Antiemetic treatment consisted of a single dose of ondansetron (0.6 milligrams per kilogram (mg/kg)) given intravenously (IV) prior to chemotherapy (n=16) or 0.15 mg/kg IV every 4 hours for 4 doses (n=15).

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Grids used to assist the NHS Suffolk Drug & Therapeutics Committee in reaching a decision about new medications

For many years scientists have recognised two types of research: ♦ Primary: original studies, based on observation or experimentation on subjects. ♦ Secondary: reviews of published research, drawing together the findings of two or more primary studies. In biomedical science there is general agreement over a hierarchy: the higher up a methodology is ranked, the more robust and closer to objective truth it is assumed to be. The orthodox hierarchy looks something like this-

Rank: Methodology Description

1 Systematic reviews and meta-analyses Systematic review: review of a body of data that uses explicit methods to locate primary studies, and explicit criteria to assess their quality. Meta-analysis: A statistical analysis that combines or integrates the results of several independent clinical trials considered by the analyst to be "combinable" usually to the level of re- analysing the original data, also sometimes called: pooling, quantitative synthesis. Both are sometimes called "overviews."

Randomised controlled trials Individuals are randomly allocated to a control group and a group who receive a specific 2 (finer distinctions may be drawn within this intervention. Otherwise the two groups are identical for any significant variables. They are group based on statistical parameters like the followed up for specific end points. confidence intervals)

3 Cohort studies Groups of people are selected on the basis of their exposure to a particular agent and followed up for specific outcomes.

4 Case-control studies "Cases" with the condition are matched with "controls" without, and a retrospective analysis used to look for differences between the two groups.

5 Cross sectional surveys Survey or interview of a sample of the population of interest at one point in time

6 Case reports. A report based on a single patient or subject; sometimes collected together into a short series

7 Expert opinion A consensus of experience from the good and the great.

8 Anecdotal Something a bloke told you after a meeting or in the bar. Adapted from Systematic reviews, What are they and why are they useful? ScHARR 2008 To Decide if a Medication Is To Be Used In Suffolk

Criterion to be measured Tends to poor 2 Medium 4 Tends to good Quality of evidence in the papers reviewed 7 - 8 5 - 6 3 – 4 2 1 Magnitude of effect inferred from trials reviewed Low Medium High Are trial end-points surrogate markers or clinical outcomes? Clinical outcomes Clinical usefulness of trial end-points x Known Side Effect Profile High Medium Low Known Interactions High Medium x Low Concern re Possible Side Effects Not Yet Uncovered High Medium Low Balance of Benefit To Harm (side effects toxicity interactions etc) Poor Medium Good NNT High Medium Low Comparison Of Effectiveness With Other Medicines In Use For The Poor Medium Good Same Condition Severity of Condition to be Treated Trivial Medium x Severe Novel drug or member of existing class Existing class Uptake (estimated proportion of people with this condition likely to Variable be prescribed the medication under consideration – maximum and minimum uptake) Is the drug to be used in Suffolk?

Prescriber’s Rating Definitions Bravo! -The drug is a major therapeutic advance in an area where previously no treatment was available. A real advance - The product is an important therapeutic innovation but has certain limitations. Offers an advantage - The product has some value but does not fundamentally change present therapeutic practice. Possibly Helpful - The product has minimal additional value, and should not change prescribing habits except in rare circumstances. Judgement reserved - The Committee postpones its judgement until better data and a more thorough evaluation of the drug are available. Nothing New - The product may be a new substance but is superfluous because it does not add to the clinical possibilities offered by previous products available. In most cases these are “me-too” products. Not acceptable - Product without evident benefit over others but with potential or real disadvantages. (With acknowledgement to Prescrire) To Decide Where A Medication Is To Be Used In Suffolk

Criterion Red Amber Green Blue Skills of the Experience Of The Condition Specific Specific Specific Genera prescriber Diagnosis Specific Specific Specific General Monitoring Progress Of Treatment Difficult Specific Genera Genera

Therapy Patient Selection Difficult Specific Specific Easy Initiation Of Treatment Difficult Difficult Easy Easy Dose Titration Difficult Specific Easy Easy Monitoring Of Side Effects Complex Easy Easy Easy Method Of Administration Complex Normal Normal Normal Discontinuation Of Treatment Complex Complex Easy Easy

References Jonsen A. Bentham in a box: Technology assessment and health care allocation. Law Med. Health Care. 1986;14:172-174 1 Suffolk Drug & Therapeutics Committee Responsibility for prescribing, Hospital Trust or GP Attached as Appendix 1 & Appendix 2

QIPP Rating: - not cost effective in Primary Care