The elderly are more sensitive to the actions of certain drugs due to changes at the receptor level, which includes changes in receptor binding, a decrease in the number of receptors, and altered biochemical reactions initiated by receptors. In general, the elderly are more sensitive to medications acting on the central nervous system-commonly leading to sedation, dizziness, and confusion. Sympathetic and parasympathetic response is impaired due to changes in receptor function. This fact likely explains the orthostatic hypotension commonly seen in the elderly. In addition, age-related decrease in response to cholinergic receptors affects anticholinergic drug response e.g. urinary retention ; .9-13. Preliminary data from study 039 suggested that cardiovascular reactions and seizures may be more frequent in the bortezomib group compared to dexamethasone. Patients with risk factors for seizure activity e.g., hyponatremia, need to be monitored for this event. Although not commonly reported as a serious adverse event, bortezomib treatment can cause orthostatic postural hypotension. These events are observed throughout therapy and are not acute reactions associated with bortezomib administration. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. The management of orthostatic postural hypotension may include adjustment of antihypertensive medications, hydration, or administration of mineralocorticoids. The Applicant has highlighted the rare cases of tumour lysis syndrome, since they illustrate specific management principles in patients at risk. Bortezomib is cytotoxic and in patients with a high tumour burden, additional hydration, allopurinol, and close observation are advised. Asymptomatic increases in amylase has been reported rarely. The Applicant has recently reviewed the safety database and has found no evidence of any signal for pancreatitis. Careful monitoring of blood amylase levels will continue. Hepatitis elevation in liver enzymes ; has been recently reported in a small number of patients; the Applicant will continue to closely monitor for this event to evaluate potential risk factors or etiology. The Applicant argues that no clear relationship was found between the level of proteasome inhibition and the incidence of adverse events. This is not totally unexpected, since proteasome inhibition was measured one hour after bortezomib administration. An analysis of relationship between trough level of inhibition and adverse events would have been more appropriate. A correlation with cumulative dose and many of the key adverse events was found. During the update period hypoglycaemia has been reported 1% ; and has been included in the SPC. Two of the patients were diabetics who had a history of stable control prior to bortezomib and required dose reduction of antidiabetic medication. A cautionary sentence was added in Section 4.4 of the SPC regarding concomitant use with oral hypoglycaemics, and appropriate information in section 4.5. It is unclear if this is a pharmacodynamic and or pharmacokinetic interaction. Bortezomib was not studied in children and in patients with impaired renal or hepatic function. Only few data are available from post-hoc analyses in patients with kidney or liver function impairment. No formal pre-planned ; PD and PK studies were undertaken on special populations, to evaluate the effect of age, gender, race or organ function such as liver or kidney ; . The assessment of safety in special populations rests on such sub-group analyses, which are of limited value due to the small number of patients studied. This lack of data is of concern especially in patients with renal insufficiency, a condition frequently present in MM patients. Available data are only based on 10 patients with creatinine clearance 30mL min. These reportedly had the same type or severity of adverse events reported in the overall study population, in which however the incidence of serious adverse events, cardiac disorders, and neutropenia increased with decreasing renal function. Due to lack of experience, severe renal impairment should be listed as a contraindication. The same applies to liver impairment, which is expected to have a major impact on pharmacokinetics. Bortezomib treatment may be associated with immunological events e.g. immunocomplex-mediated reactions ; . Three individual reactions described may represent immunocomplex-mediated reactions. It should be noted that in 2 of the 3 patients, treatment with bortezomib was continued after symptom resolution with no recurrence of these symptoms. One patient, who had received 1.04mg m2 in a Phase I study, experienced an immunocomplex-mediated hypersensitivity reaction, described as a serum sickness reaction and classified as severe, with maculopapular rash and dyspnea, which resolved within one week after treatment with prednisone. Another patient experienced rapidly progressive acute renal failure with proliferative glomerulonephritis as determined by renal biopsy ; with no obvious precipitating cause after completion of treatment in Cycle 3. Renal failure resolved after treatment with IV methylprednisolone followed by oral prednisone. The third patient experienced diffuse polyarthritis concurrent with an erythematous rash after completion of Cycle 3. The patient received treatment with prednisone, and the event resolved. No drug-drug interactions studies were conducted. Reports of haemolytic anaemia, deafness hypoacusis and inappropriate ADH secretion have been received, and the applicant has committed to discuss causality in the first periodic safety update report.

Haematologica 2005; 90 suppl 2 ; : 15 kropff mh, bisping g, wenning d, volpert s, tchinda j, berdel we, kienast j: bortezomib in combination with dexamethasone for relapsed multiple myeloma and buspirone.

Methods: patients with metastatic melanoma and adequate hematologic, renal, and hepatic function were treated with bortezomib a 5-mg m2 intravenous bolus twice weekly for 2 of every 3 weeks and bortezomib. Proportion of use of higher-cost vs. lower-cost products ; . Inflation and mix influence price per pharmacy claim. In this therapy class, the mix effects are small and the costs per pharmacy claim for the 4 MS medications are relatively equivalent Table 2 ; . The compound inflation increase in unit price of 9% to 13% mirrored the 13% annualized increase in price per claim Table 2, Figure 3, Table 3 ; . Therefore, the cost trend for these medications is primarily a function of price inflation and utilization. As shown in Figure 3, which represents claims for approximately 3 million members for whom continuous data were available over the past 3 years, per capita utilization number of claims per 100, 000 members per month ; has remained relatively stable since 2004. AWP ingredient cost per claim produced most of the increase in total per capita expenditure AWP per member per month [PMPM] ; . As the quantity dispensed per claim decreased slightly throughout this time frame, price inflation was the major driver of the increase in expenditure. AWP was used in these analyses because contract rates with pharmacies are confidential and only brand-name products are included in this analysis. In addition, according to the U.S. Congressional Budget Office, "AWP tends to have a consistent relationship with average transaction prices for [brand] drugs."12 From the first quarter of 2004 through the third quarter of 2007, the compound annualized increases in AWP PMPM expenditure, AWP ingredient cost per claim, and number of claims per 100, 000 members per month for self-injectable MS medications were 13.6%, 13.0%, and 0.5%, respectively Table 3 and Figure 3 ; . Over the 45-month period, the percentage of all pharmacy expenditures that were attributable to self-injectable MS medications increased from 1.8% to 2.5%. In the third quarter of 2007, absolute values for MS self-injectable AWP PMPM spend, AWP price per claim, and number of claims per 100, 000 members per month were .74, , 119, and 82.2, respectively. Therefore, of every of pharmacy benefit dollars is spent on self-injectable MS medications, and volume is 82.2 claims per month per 100, 000 insured members and busulfan.

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