Miscellaneous Hormones

C H A P T E R

43 Miscellaneous Hormones Michael T. Bowen Faculty of Pharmacy, University of Sydney, NSW, Australia; School of Psychology, Faculty of Science, University of Sydney, NSW, Australia E-mail: [email protected]

CALCITONIN [SED-15, 595; SEDA-33, 909; SEDA-34, 703; SEDA-35, 789] Placebo-controlled trial A randomised, placebo-controlled trial of 6 months of nasal salmon calcitonin (200 IU/day) in combination with 500 mg calcium per day for the treatment of 60 patients who underwent total hip arthroplasty found that treatment was well tolerated with no serious side effects or discontinuation of medication reported [1C]. Oral versus nasal calcitonin Women aged 46–86 years with postmenopausal osteoporosis participated in a randomised, double-blind, phase III trial of 48 weeks of treatment with oral (0.2 mg per day; n = 263) versus intranasal (200 IU per day; n = 182) calcitonin compared to placebo (n = 104) [2C]. The majority of adverse events were mild or moderate in intensity with the most common in the oral treatment, nasal spray and placebo groups being abdominal pain (27.8%, 23.6% and 26.9%, respectively) and nausea (12.2%, 8.2% and 6.7% respectively). Serious adverse events were reported more frequently in the oral treatment group (7.6%) and placebo group (8.7%) than in the nasal spray treatment group (4.9%). As patients receiving the placebo oral treatment also experienced more adverse events, it is possible that the formulation of the treatment was involved rather than the calcitonin compound. Significantly fewer women in the oral tablet treatment group versus the nasal spray treatment group had antibodies directed against salmon calcitonin in sera samples taken at weeks 12 and 48 of treatment (6.5% vs 32.5%, on average). There were too few antibody-positive subjects to draw definitive conclusions. Reviews A review of antiresorptive therapies for osteoporosis identified the following as the most commonly reported adverse effects of calcitonin therapy: irritation of the nasal passage; nasal mucosal erythema and minor bleeding; sneezing; rhinitis; and nausea [3R]. Across studies these side effects generally occurred in less than 10% of patients receiving calcitonin treatment. In a meta-analysis examining the efficacy of calcitonin for the treatment of acute and chronic pain related to recent and remote osteoporotic vertebral compression fractures (OVCF), the authors concluded that calcitonin has proven efficacy in the management of acute back pain associated with a recent OVCF but that there is no convincing evidence supporting the use of calcitonin for chronic pain associated with a remote OVCF [4M]. The 13 studies included in the meta-analysis reported 85 (18.1%) patients receiving calcitonin experiencing side effects (primarily enteric disturbances (47%) and flushing (32%)) and 19 (4%) receiving placebo (the majority due to enteric disturbances (68%)). The pooled random effects model indicated a relative risk of experiencing side effects of 3.09 (95% CI = 1.80–5.32, p < 0.0001) and a NNH of 12. The side effects were generally reported as being mild.

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Withdrawal of FDA and EMA approval due to cancer risk On March 5, 2013 the Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee of the U.S. Food and Drug Administration voted 12 to 9 against continued marketing of calcitonin nasal spray for the treatment of osteoporosis in women greater than 5 years after menopause [5S]. The 9 panel members in favour of keeping calcitonin on the market argued that it has particular efficacy in niche populations such as the elderly and those suffering acute pain from vertebral fractures. The 12 panellists who opposed continuing marketing of calcitonin cited its limited efficacy being outweighed by the compounds emerging carcinogenic properties as the primary reason for their decision. It should be noted that all panel members agreed that the cancer signal was weak, but that it had to be taken seriously. The European Medicines Agency’s Committee for Medicinal Products for Human Use came to a similar decision on July 19, 2012 which was upheld on November

15, 2012 following re-examination [6S]. The committee completed a review of the benefits and risks of calcitonincontaining medicines and issued a recommendation that salmon calcitonin should no longer be used to treat osteoporosis, citing limited efficacy and a 2.4% higher risk of cancer in patients using nasal spray calcitonin versus placebo and a 0.7% greater risk of cancer in patients using oral formulations. The committee concluded that calcitonin should only be made available as a solution for injection or infusion at the ­lowest effective dose for:

  

• Prevention of bone loss due to sudden immobilisation with a recommended treatment duration of 2 weeks and a maximum treatment duration of 4 weeks. • Treatment of Paget’s disease where patients are nonresponsive to, or are unable to take, alternative treatments. Treatment should normally be limited to 3 months. • Treatment of hypercalcaemia caused by cancer.   

Treatment of refractory mania A randomised, double-blind, placebo-controlled study of the efficacy of 3 weeks of adjunctive nasal spray calcitonin (200 IU per day) for treating refractory mania (N = 46) did not support the use of nasal calcitonin for this indication [7c]. Rhinorrhoea and nasal inflammation were reported more commonly in the treatment group (6/22) than in the placebo group (2/24).

GONADOTROPINS (GONADORELIN, GnRH AND ANALOGUES) [SED-15, 1536; SEDA-33, 909; SEDA-34, 703; SEDA-35, 789] Clinical trial A phase II clinical trial found that leuprolide did not have efficacy in reducing premature ovarian failure in women undergoing haematopoietic stem cell transplantation [8c]. Nine of the 59 patients declined the ­second dose of leuprolide due to intolerable menopausal side effects (hot flushing, atrophic vaginitis and mood swings). No permanent or grade 4 side effects were observed in any of the participants. Anaphylaxis A Japanese man with no history of allergies developed anaphylaxis to leuprorelin acetate depot while receiving treatment for metastatic prostate cancer [9A].   

  

In 2001 the man, aged 68, received subcutaneous injection of a 3.75 mg 1-month leuprorelin acetate depot. At the sixth injection, a local skin reaction with erythema and induration was observed at the site of injection. This initial reaction resolved without treatment. A similar reaction was observed following the seventh and eight injections leading to discontinuation of treatment. Due to an increase in PSA levels, injection of depots resumed in 2006 upon the patient’s request. Approximately 30 min after injection, the patient lost consciousness and presented with cyanosis with generalised urticaria. The patient was diagnosed with anaphylactic shock by leuprorelin acetate depot injection and was immediately treated. The patient made a full recovery and was discharged from hospital after 2 days of conservative treatment. One month after the reaction, a d ­ ruglymphocyte stimulation test (DLST) was conducted and it was determined that the patient was sensitised to leuprorelin and the vehicle used for the 1-month depot (polylactic and glycolic acids) but not to the vehicle used for 3-month depots (polylactic acid). The authors note that a review of the literature revealed five other case reports of anaphylaxis to GnRH depot [10–14A] and that at present there is no apparent predictive parameter for anaphylaxis. DLST is preferred to skin testing as previous studies have reported acute symptoms requiring treatment following skin testing [10A]. The DLST in the present study indicates that leuprorelin and/or the vehicle used in the depot could be the cause of anaphylaxis.

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Onset of anaphylaxis can occur within 30 min after exposure or up to 6 h after injection of the depot. Given the potential for a fatal reaction, patients should be monitored carefully for anaphylaxis for several hours following depot injection. Observational study Retrospective analysis was performed on a group of patients, 28 of whom underwent uterine artery embolisation (UAE) without GnRH agonist pretreatment, 12 of whom received GnRH agonist treatment 1–5 times before UAE [15c]. The final mean volume reduction rate of the major fibroids at 1–3 months post UAE was significantly higher in the group that received GnRH agonist pretreatment. The incidence of adverse events and complications (minor, major or grade D) did not differ in prevalence or type between the two groups. GnRH agonists for lowering testosterone in sex offenders GnRH agonists are increasingly being prescribed to sex offenders due to their ability to reversibly reduce testosterone levels and evidence from open and uncontrolled studies that this may lead to a reduced rate of recidivism. Thirty-two treatment institutions in Germany reported on 57 sex offenders receiving GnRH agonist treatment [16c]. The most commonly reported side effects in these patients were weight gain (19.3%), gynaecomastia (12.3%), hot flushes (47.4%), reduced body hair (29.8%), hypogonadism (3.5%), bone mineral density loss (14%) and localised pain at the injection site (33.3%). The authors attributed the majority of the side effects to lowered testosterone as a result of treatment.

GONADOTROPHIN-RELEASING HORMONE ANTAGONISTS [SED-15, 1535; SEDA-34, 704; SEDA-35, 790] Comparative studies A randomised, open-label trial comparing degarelix (n = 84) with goserlin (n = 98) in the treatment of prostate cancer patients found that the two treatments were equivalent in their ability to induce the primary goal of prostate volume reduction but the former was significantly more efficacious in treating lower urinary tract symptoms [17C]. Injection-site reactions (primarily pain, 14%; erythema, 4% and swelling, 4%) occurred only in degarelix-treated patients. Other relatively common reactions were hot flushes (degarelix, 10%; goserelin, 17%), erectile dysfunction (degarelix, 5%; goserelin, 4%) and hyperhidrosis (degarelix, 4%; goserelin, 5%). A phase III, multicenter, open-label, randomised study found that ganirelix (0.25 mg per day) was more efficacious than triptorelin (0.05 mg per day) treatment in Chinese women undergoing fertility treatment (N = 233) [18C]. There was a trend towards significantly fewer ganirelix-treated patients discontinuing before embryo transfer (ganirelix, 8%; triptorelin, 15%; p = 0.1). It was found that 7.5% of patients in the triptorelin group were discontinued due to risk of ovarian hyperstimulation syndrome and only 1.8% in the ganirelix group (p = 0.06). In the ganirelix group, 22.3% of patients experienced at least one adverse event compared to 18.3% in the triptorelin group. Nausea was the most frequently cited adverse event (ganirelix, 8%; triptorelin, 9.2%). Ongoing pregnancy rates were equivalent (ganirelix, 39.8%; triptorelin, 39.2%), although the incidence of twin pregnancies were higher in the triptorelin group (44.7% vs 22.2% in ganirelix group). This study suggests that in Chinese women undergoing fertility treatment, ganirelix may be more efficient, equally effective and a potentially safer option than triptorelin treatment. No side effects of treatment were reported by 13 women receiving treatment with the GnRH antagonist Cetrotide (2 × 250 µg SC doses) for early-onset ovarian hyperstimulation syndrome in a nonrandomised outpatient study [19c]. Systematic review A systematic review of clinical trials examining the efficacy of degarelix in the treatment of prostate cancer [20M] found that injection-site reactions appeared more frequently in patients treated with degarelix (40%) than in patients treated with leuprolide (<1%; p < 0.001). Chills were also more common with degarelix (4%) than leuprolide (0%; p < 0.01). Conversely, adverse events more frequently observed in the leuprolide-treated patients were urinary tract infection (9% vs 3%, p < 0.01) and musculoskeletal and connective tissue adverse events (26% vs 17%, p < 0.05). The authors identify the quicker onset of therapeutic testosterone with degarelix, and the avoidance of supraphysiological testosterone surges observed with GnRH agonists, as of particular clinical importance as it avoids the potential of surge-induced cancer stimulation and clinical flare found with GnRH agonists.

SOMATROPIN (HUMAN GROWTH HORMONE, hGH) [SED-15, 3163; SEDA-33, 910; SEDA-34, 704; SEDA-35, 791] Sleep apnoea A longitudinal observational study of 50 children (26 female; median age 1.9 years at the start of the study) with Prader–Willi syndrome (PWS) was conducted to assess the association between long-term growth hormone therapy, adenotonsillar tissue hypertrophy and obstructive sleep apnoea [21C]. The number of patients with an obstructive apnoea hypopnoea index (OAHI) > 1 (considered pathological obstructive sleep) increased from 3 to 22,

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36 and 38 going from baseline to, 6 weeks, 6 months, 12 months, 2 years and 4 years into growth hormone therapy (p < 0.05). Treatment was temporarily suspended for three patients due to severe obstructive sleep apnoea. There was a significant increase in the incidence of severe adenoid hypertrophy (by 24%) and tonsil hypertrophy (by 15%) from baseline to 2 and 3 years into treatment. One patient required adenotonsillectomy at 1 year and two patients at 4 years. The age-adjusted size of adenoids was significantly positively correlated to OAHI severity, indicating GH therapy-related increases in adenoids and tonsils are likely resulting in the obstructive sleep apnoea due to their obstruction of the nasal airways. This study highlights the need for annual polysomnography and adenotonsillar evaluation in children undergoing long-term GH treatment for PWS. In a randomised, multicenter, placebo-controlled study, female patients (N = 120) with fibromyalgia who received 0.006 mg/kg/day of GH subcutaneously for 6 months in addition to standard fibromyalgia treatment had reduced pain compared to those receiving placebo [22C]. In general, the addition of GH treatment to standard therapy was well tolerated. Only one serious adverse event, sleep apnoea syndrome, was considered GH treatment-related. The most common GH-related adverse events were headache, oedema in lower extremities and carpal tunnel syndrome. Metabolic changes An open-label, multicenter study of 26 or 52 weeks of treatment with sustained-release GH formulation LB03002 in 136 GH-deficient adults had three withdrawals due to adverse events (asthenia, ­peripheral oedema and dysgeusia) [23C]. The most common treatment-emergent adverse events were nasopharyngitis, ­arthralgia, peripheral oedema, headache and injection-site reactions. Treatment-emergent diabetes mellitus (fasting glucose >126 mg/dL) was reported in five patients. The long-term effects of recombinant human GH (rhGH) therapy were assessed in 98 Dutch GH-deficient adult patients who had been treated for at least 10 years (mean age 59.4 years; 50% female) [24c]. Treatment was associated with improvement of some cardiovascular features, however, the prevalence of metabolic syndrome after 10 years of treatment (57.1%) was significantly increased relative to baseline (32.7%) and the overall metabolic syndrome prevalence for that age group in the Dutch population (29–41%) [25C]. As a nontreatment control group was not included in this longitudinal study for obvious ethical reasons it is difficult to determine whether this increased prevalence was a feature of the treatment or the condition, although higher prevalence of metabolic syndrome in untreated ­GH-deficient adults has previously been reported [26C]. Children (mean age = 8.55 years; 72% male) with non-GH-deficient short stature were randomised to receive 12-month treatment with GH (n = 114) or to observation (n = 37) [27C]. Increased fasting serum insulin levels were observed in the GH treatment group relative to the observation group, but they remained within the normal reference range for both groups. Longer treatment regimens should monitor fasting serum insulin levels to ensure that they stay within the normal range. A randomised, placebo-controlled study of the enduring effects of 6 months of GH treatment in 39 obese premenopausal women found that fasting glucose levels were elevated but did not reach the diagnostic criteria for diabetes (>7 mmol/l) in any patients throughout the study [28c]. Four subjects receiving GH had 2 h oral glucose tolerance test results that met the criteria for diabetes (>11.1 mmol/l). These levels were normalised by 3 months after treatment cessation. A prospective, dose–response study of 11 patients examined the longer-term dose–response to GH therapy in prepubertal (aged 3–16 years) GH-deficient children [29c]. One case of hyperglycaemia and one case of glycosuria were reported during the first 24 months of treatment. A meta-analysis was performed on eight studies examining the safety and efficacy of GH treatment in adults with PWS (75 men and 59 women) [30M]. There was a small but significant increase in fasting plasma glucose levels after 12 months of GH therapy (mean increase = 0.27 mmol/L) and a trend towards increased fasting insulin levels (mean increase = 20.24 p/ml/l) and HOMA-insulin resistance (IR) scores (mean increase = 0.6). One patient with diabetes mellitus withdrew due to worsening glycaemic control and 12 patients developed impaired glucose tolerance after 12 months of GH treatment. The most commonly reported adverse event was oedema (20/134 patients). Thirty children (83% male; mean age =12.4 years) undergoing long-term glucocorticoid treatment for chronic disease were randomised to receive 6 months of GH treatment or no GH treatment, after which all patients received 6 months of GH treatment [31c]. One patient with nephrotic syndrome reported headache after the first 6 months of treatment which was likely due to water retention. GH treatment was ceased for 2 weeks and then steadily restarted in increasing doses without further incidence. Fasting and 2-h postprandial glucose levels were significantly higher after 12 months of GH therapy, with five patients exhibiting impaired glucose tolerance. No patients met the diagnostic criteria for diabetes. Forty-six adults with PWS (54% female; median age = 30 years) were randomised to receive GH therapy or placebo for 1 year, followed by 2 years of open-label GH treatment [32c]. One patient in the GH treatment arm of the study was withdrawn due to progression of diabetes and three patients with impaired glucose tolerance at

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baseline developed diabetes. Headaches were reported in two patients receiving treatment. Two patients developed mild oedema while four had worsening of pre-existing oedema over 2 years of GH treatment. One patient treated with GH was diagnosed with carpal tunnel syndrome and underwent surgery. On average, no significant changes in fasting glucose, fasting insulin or HOMA-IR were observed during the placebo-controlled or openlabel phase. A relatively small (0.2%) increase in HbA1c was observed in patients who underwent 2 years of GH therapy (p = 0.01). Sixty-eight prepubertal children with cystic fibrosis were randomised to receive either GH therapy or no treatment for 12 months followed by 6 months of observation in an open-label, multicenter study [33c]. The number of adverse events did not differ between GH-treated and nontreated patients. Ten subjects in the GH group had adverse events that were likely to be drug-related: Seven injection-site reactions; five cases of hyperglycaemia with one subject discontinued; and one case of papilloedema and headache following 5 months of treatment resulting in discontinuation. The latter was believed to be due to drug-related benign intracranial hypertension and the symptoms resolved shortly after treatment discontinuation. Recommendations by an expert panel A multidisciplinary panel of 43 experts performed a systematic review of the literature to formulate recommendations for the use of rhGH in children and adult patients with PWS [34R]. With regards to safety, the panel concluded that patients with severe obesity, uncontrolled diabetes mellitus, untreated severe obstructive sleep apnoea, active cancer or psychosis should be excluded from GH treatment. Due to epidemiological data suggesting a link between IGF-I levels and particular adverse events, the panel recommends that IGF-I levels be maintained within normal range (0 to +2 SDs for adults, +1 to +2 SDs for children). The panel recommended that the following potential side effects of rhGH treatment be routinely monitored throughout treatment: changes in physical features and body proportions, or bone growth; peripheral oedema; joint pain; sleep apnoea/disordered breathing (snoring, respiratory pauses, excessive daytime sleepiness); intracranial hypertension (headache, visual changes, dizziness, nausea); slipped capital femoral epiphysis; elevated fasting insulin; decreased T4 levels; type 2 diabetes; and intracranial bleeding/stroke. Omnitrope A Swedish study of 98 children (53% male; aged 1–15 years) undergoing GH treatment with originator rhGHs (e.g. Genotropin®) were switched to the biosimilar rhGH Omnitrope® [35C]. There was no change in expected treatment outcomes following the switch and there were no serious or unexpected adverse drug reactions. Cost of treatment of was 2/3 of that with the originators. The longitudinal, postmarketing, observational PATRO children study (N = 1837, mean age = 9.33 years, 56.9% male) found that adverse events associated with Omnitrope® with an incidence rate >0.001 (based on 2851.16 patient years) were headache, hypothyroidism, arthralgia, pain in extremity, injection-site haematoma, decreased glucose tolerance, asthenia, injection-site pain, increased blood creatine, phosphokinase and myalgia [36C]. There were no confirmed cases of diabetes (type 1 or 2) or malignancy related to treatment and no anti-hGH antibodies have been found in a subset of 30 patients. Carcinogenicity A case study of a husband and wife (both Caucasian and 49- and 51-years-old, respectively) reported their diagnosis with melanoma 3 months and 2.5 months after commencing hGH treatment, respectively [37A]. Given the unlikelihood of two unrelated people developing melanoma within such a short time frame a common environmental component must be considered. hGH has previously been implicated in promoting malignant melanocytic neoplasm growth [38C] and thus it is possible that hGH contributed to the co-temporal development of melanoma in these patients. More definitive data are required to determine the relationship between hGH and melanoma, but these cases suggest that increased surveillance is warranted, especially in high-risk patients. A case study reported the development of rare intracranial endothermal sinus tumours in a 15-year-old girl who had been undergoing GH therapy for 17 months due to GH deficiency [39A]. The girl presented with nausea, ­headache and vomiting and the presence of two tumour masses were identified by magnetic resonance imaging. Cause–effect cannot be attributed but the possibility of GH treatment-related malignancy should be considered, especially when patients present with the aforementioned symptoms. Longitudinal study A longitudinal, randomised, dose–response GH trial was conducted to assess the efficacy of GH treatment in children short-for-gestational-age (N = 121; 50.4% female; mean age 11.2 years) when treatment is started during adolescence [40C]. GH treatment was effective in improving adult height and no adverse events considered to be drug-related were observed. Scoliosis A multinational, retrospective, observational study of 41 prepubertal children (mean age 3.8 years) with PWS was conducted to assess the safety and efficacy of long-term GH treatment (mean duration 4.1 years) [41c]. Treatment was associated with significant improvements in height and body composition. Adverse events that may have been related to GH treatment were scoliosis (8/41) and sleep apnoea (3/41). Of note, 3/8 children reporting scoliosis during the study also presented with the condition at baseline.

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Placebo-controlled trial A phase II, randomised, placebo-controlled, double-blind, clinical trial testing the efficacy of 12 months of GH treatment in 40 patients (53% male; mean age = 62.7 years) with amyotrophic lateral sclerosis found that the incidence of adverse events did not differ significantly between placebo and treatment groups [42c]. Renal transplant rejection A systematic review and meta-analysis was performed on five randomised, controlled trials assessing the safety and efficacy of GH treatment for improving growth in a total of 401 children who had undergone renal transplant [43M]. Overall, GH treatment improved growth. Based on the pooled data, the renal transplant rejection rate trended towards being higher in the treatment group (17.1%; 35/205) than in the control group (10.3%; 19/185), RR = 1.56, 95% CI: 0.97–2.53, p = 0.07. Two of the five included trials found that having had more than one rejection episode prior to commencement of GH therapy was predictive of increased risk of allograft rejection after commencement of treatment. High-quality clinical studies are required to further assess the possible link between GH therapy and transplant rejection as the nonstatistically significant trend towards heightened risk identified in this meta-analysis makes it difficult to draw a definitive conclusion. Systematic review A systematic review of three randomised, controlled trials (N = 162) of GH treatment for hip fractures concluded that overall quality of current evidence is low and thus it is difficult to make any conclusive assessment of GH treatment efficacy in the target patient population [44M]. There were no statistically significant differences in the number of adverse events reported by GH-treated versus placebo-group patients across the three studies. Increased intraocular pressure An observational study found that children treated with GH for at least 12 months (N = 55, mean age = 11.4, 67% male) had increased intraocular pressure compared to a control group of children examined prior to initiation of GH treatment (N = 24, mean age = 10.3 years, 87% male) [45c]. Although the elevated levels in the treated group were still within the normal range, this study suggests increased intraocular pressure may be a side effect of longer-term GH treatment and this should be examined closely in future trials in both children and adults.

GROWTH HORMONE RECEPTOR ANTAGONISTS [SEDA-33, 911; SEDA-34, 708; SEDA-35, 792] Exon 3-deleted GHR A cross-sectional, multicenter study of 127 acromegalic patients did not find any association between exon 3-deleted GHR (d3GHR) and efficacy or adverse reactions to pegvisomant treatment [46C]. d3GHR patients did deviate from the Hardy–Weinburg equilibrium which the authors conclude required further investigation to determine whether this may be associated with poor response to pegvisomant. New formulation In an open-label, randomised, single-dose, two-way crossover, phase I study of healthy male and female subjects (N = 28), the safety and tolerability of a new 1 × 30 mg/ml subcutaneous injection formulation of pegvisomant did not differ from the marketed 2 × 15 mg/ml subcutaneous formulation [47c]. The new formulation may serve to minimise injection-site reactions by decreasing the number of injections required for effective treatment, although larger studies are required to properly assess this possibility. Elevated intrahepatic lipid A randomised, controlled trial (N = 18) of pegvisomant combined with somatostatin analogue treatment versus somatostatin analogue monotherapy found that co-treatment with pegvisomant resulted in elevation of intrahepatic lipid which could account for the transient elevation in liver enzymes observed in up to 25% of patients undergoing pegvisomant treatment [48c]. Lipohypertrophy Case studies of two Caucasian women (aged 51 and 71 years) with acromegaly with pegvisomant-related lipohypertrophy at the abdominal injection site found that switching the injection site to the two thighs resulted in reversal of the lipohypertrophy at the abdominal injection site but re-emergence at the new injections sites [49A]. These cases indicate that injection-site lipohypertrophy appears to be reversible and could be minimised through careful monitoring by physical and radiological examination and regular rotation of injection site.

MELATONIN AND ANALOGUES [SED-15, 2245; SEDA-33, 912; SEDA-34, 709; SEDA-35, 792] Literature reviews A review of the literature on the use of melatonin to treat sleep disorders concluded that treatment is not associated with any significant or serious short-term or long-term adverse side effects and that the headache, confusion, dizziness, cough and rashes sometimes reported are common symptoms in children and are most

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likely coincidental or due to impurities in the often unregulated formulations of melatonin that people acquire [50R]. Reports of poor seizure and asthma control, and endocrinological issues in puberty have not been confirmed in the randomised controlled trials that have been conducted. A review examining evidence for melatonin affecting seizure control found that, based on current studies, there does not appear to be an association [51R]. However, very few studies have been conducted and large, well-designed randomised, controlled trials are required before firm conclusions can be drawn. Randomised trials A randomised, placebo-controlled trial of controlled-release melatonin (3 mg) for treating insomnia in children (N = 160, mean age = 6.6 years, 82% male) reported that the melatonin treatment was well tolerated with no adverse effects reported or observed and normal blood and urine analyses recorded across treatment groups [52C]. A randomised, placebo-controlled trial examining the efficacy of melatonin (20 mg) in the treatment of cachexia in 73 advanced cancer patients found that it did not improve appetite, weight or quality of life compared with placebo [53C]. Despite the high dose of melatonin there was no difference between the conditions in the prevalence or type of adverse events reported. A randomised, placebo-controlled trial examining the efficacy of immediate release melatonin (0.5–12 mg, depending on response) in treating sleep disorders in 146 children (aged 3–15 years) with neurodevelopmental disorders found melatonin caused mild improvements in total sleep but more marked improvement in latency to sleep and actigraphy results [54C]. However, treatment was associated with earlier waking times. Only mild adverse events were reported and their occurrences were similar between the two groups—no formal statistical assessment of ­prevalence was conducted. A randomised, placebo-controlled trial of 4-month oral melatonin (3 mg) in postmenopausal breast cancer survivors (N = 95) found melatonin had no impact on circulating oestradiol, IGF-1 or IGFBP-3 levels [55C]. Compliance was high and comparable between the two groups (43/48 for the melatonin group vs 42/47 for the placebo group). No grade 3 or 4 adverse events were reported and the adverse events reported did not appear to differ in prevalence or type between treatment and placebo groups. Tolerance A randomised, placebo-controlled trial examining 67 haemodialysis patients suffering subjective sleep problems found that melatonin treatment (3 mg per day) resulted in improved sleep efficiency and actual sleep time on haemodialysis days but none of these benefits remained after 12 months of treatment, suggesting melatonin may not be efficacious for treating sleep disturbances in this population in the long term [56C]. A randomised, placebo-controlled trial examining 3 weeks of melatonin treatment (2.5 mg) for the treatment of sleep disturbances in 16 hypertensive patients (aged 45–64 years; 56% female) treated with beta-blockers found that melatonin treatment was effective at improving sleep quality with no adverse side effects, tolerance or rebound insomnia observed [57c]. Open-label trial An open-label, escalating-dose trial of melatonin in the treatment of sleep disorder in 24 children (aged 3–9 years) with autism found that 1 and 3 mg melatonin improved sleep latency in most children [58c]. Overall the treatment was well tolerated and safe with only one mild adverse event (loose stool) reported that may have been related to the melatonin preparation.

OXYTOCIN AND ANALOGUES [SED-15, 2657; SEDA-33, 912; SEDA-34, 709; SEDA-35, 793] Comparative studies A randomised, controlled trial of 652 pregnant women admitted to the labour room found that sublingual misoprostol (400 μg) was significantly more effective at reducing postpartum blood loss and haemorrhage than 10 IU oxytocin intramuscular [59C]. However, side effects (nausea, vomiting, shivering and fever) were more common in the misoprostol group. A randomised, controlled trial of misoprostol (n = 100) compared to oxytocin (n = 100) in the active management of third-stage labour found that misoprostol was as effective as oxytocin but resulted in greater incidence of shivering, fever and diarrhoea [60C]. A meta-analysis of publications examining the efficacy of oxytocin versus misoprostol for reducing blood loss during caesarean section included a total of 646 pregnant women in the analysis and found that, overall, there did not appear to be a substantial difference between the efficacies of the two treatments [61M]. However, the incidence of adverse effects was significantly higher in the misoprostol group than the oxytocin group (RR 1.85, 95% CI: 1.47–2.32; p < 0.00001). The primary difference was in the incidence of postoperative shivering, which was significantly higher in the misoprostol group.

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Morbidity associated with oxytocin use in labour A population study of 61,227 nulliparous women who gave birth in NSW, Australia, hospitals in 2007–2008 found that 48.5% of these women received oxytocin to induce (28.2%) or augment (20.3%) labour [62C]. On average, women receiving oxytocin were older (median age = 29.4 vs 28 years), more likely to have hypertension or diabetes, more likely to use regional analgesia during labour (65.3 vs 22.3%) and more likely to undergo caesarean delivery (29.4 vs 14.2%). After controlling for these and other confounding variables, oxytocin was associated with an ∼30% increased risk of neonatal morbidity, with similar morbidity associated with oxytocin used for induction or augmentation of labour. Similar risk was observed in hypertensive and low-risk women as to that observed overall. After adjusting for confounders, maternal morbidity was also increased with oxytocin use for augmentation (adjusted OR = 1.38, 95% CI: 1.18, 1.63) or induction

(adjusted OR = 1.54, 95% CI: 1.35, 1.78), with a trend towards risk being greater when oxytocin was used for induction. A population study in Sweden reported analogous findings [63C]. Furthermore, a case–control study of 808 women undergoing obstetric care at Stockholm South General Hospital found that oxytocin use for 195–415 min during labour was a risk factor for retained placenta (OR = 2.00, 95% CI: 1.2–3.34) and the risk became even greater with use for over 415 min (OR = 6.55, 95% CI: 3.42–12.54) [64C]. Whilst clinical trials of oxytocin have failed to find increased risk of perinatal outcomes, the findings of these studies, amongst others, suggest that in the broader population, where the strict selection and administration protocols used in clinical trials are often not present, oxytocin appears to be associated with increased risk of adverse outcomes. Given oxytocin’s integral role in labour management, focus should be placed on strict adherence to standardised treatment regimens aimed at minimising maternal and neonatal adverse outcomes.

Intranasal oxytocin A trial of intranasal oxytocin (n = 8, each subject received, in a randomised order, placebo, 24 IU and 48 IU oxytocin separated by 7 days) for treating social anxiety in males with fragile X syndrome found that 24 IU but not 48 IU oxytocin improved eye gaze frequency [65c]. No adverse events were recorded throughout the study and safety data did not differ between controls. Larger, more comprehensive randomised, placebo-controlled trials examining intranasal oxytocin in this population are required before definitive conclusions about safety and efficacy in this population can be drawn. A randomised, double-blind, placebo-controlled trial of oxytocin as an adjunct therapy to risperidone in patients with schizophrenia (N = 40, 82.5% male; mean age = 32.7 years) found that adverse events were similar between the treatment and placebo groups and that oxytocin significantly improved positive psychopathology and had a mild but significant effect on negative symptoms [66c].

Thyrotropin-Releasing Hormone and Thyrotropin See Chapter 41.

PARATHYROID HORMONE [SED-15, 2689; SEDA-33, 913; SEDA-34, 711; SEDA-35, 794] Randomised trials A randomised, controlled trial of 6 months of parathyroid hormone treatment in combination with either concurrent or sequential ibandronate over 2 years [67c] found that both treatment regimens were efficacious in increasing bone mineral density in postmenopausal women (N = 44). Seven women met the criteria for hypercalcaemia, with only one requiring reduction in treatment. Three women met the criteria for hypercalciuria. The most commonly reported adverse events were nausea (32%) and injection-site reactions (32%). A randomised, double-blind, placebo-controlled phase III trial (REPLACE) found that recombinant parathyroid hormone treatment for patients with hypoparathyroidism (N = 134) was efficacious, well-tolerated, and did not differ from placebo in the type or prevalence of adverse events [68C].

SOMATOSTATIN (GROWTH HORMONE RELEASE-INHIBITING HORMONE) AND ANALOGUES [SED-15, 3160; SEDA-33, 913; SEDA-34, 711; SEDA-35, 794] Observational study Twenty-four patients with lymphatic leaks following kidney transplantation were treated with Stilamin® (somatostatin), which was associated with decreased draining and shortened wound healing [69c]. The only adverse events associated with Stilamin® treatment were four cases of temporary hyperglycaemia.

SOMATOSTATIN (GROWTH HORMONE RELEASE-INHIBITING HORMONE) AND ANALOGUES

667

Placebo-controlled trial A randomised, placebo-controlled trial (N = 67) of preoperative somatostatin administration for the prevention of postoperative complications following the Whipple procedure found no evidence of improved efficacy with preoperative administration [70c]. Three patients experienced mild side effects (nausea and vomiting) that may have been related to somatostatin treatment. The effects of the operation made it difficult to identify and properly assess side effects of somatostatin administration. Comparative studies A randomised trial comparing long-acting release octreotide versus lanreotide autogel in the postoperative treatment of 68 patients (63% female) with acromegaly found that the two treatments had equivalent efficacy [71C]. The most common adverse events in both groups were dyspeptic complaints, abdominal pain and injection-site pain. Concomitant temporary diarrhoea was more common in the lanreotide group. No changes in kidney function or blood counts were observed, but cholelithiasis was detected in 11.1% and 9.4% of patients in the octreotide and lanreotide groups, respectively.

Octreotide [SEDA-33, 914; SEDA-34, 712; SEDA-35, 795] Drug-induced hepatitis A child with congenital hyperinsulinism undergoing long-term treatment with relatively high-dose octreotide (maximum dose 30 μg/kg/day) developed drug-induced hepatitis that resolved following discontinuation of octreotide treatment [72A]. Children with congenital hyperinsulinism undergoing long-term octreotide treatment (especially at high doses) should have their liver enzymes routinely monitored. Desensitisation treatment for hypersensitivity A 60-year-old male with acromegaly presented with a cutaneous hypersensitivity reaction to octreotide [73A]. Alternative treatment options had either failed (e.g. surgery, radiation, dopamine agonist) or he was unable to afford the high cost of the ongoing treatment (pegvisomant). The patient successfully underwent an 8-h desensitisation protocol to octreotide in the intensive care unit and the next day resumed normal octreotide treatment. In the 8 months following the desensitisation protocol, the patient denied having any allergic reaction to treatment, suggesting desensitisation to octreotide warrants further examination as a viable approach to eliminating hypersensitivity reactions to octreotide where alternative treatment options are not available. Treatment of castration-resistant prostate cancer Thirteen patients with progressive nonmetastatic castrationresistant prostate cancer underwent treatment with octreotide acetate (30 mg intramuscular every 28 days for a median of 13 weeks) [74c]. Octreotide treatment appeared to lower IGF-1 and raise IGFBP-1 levels but did not result in sustained declines in PSA. Three patients had grade 3 adverse events that were thought to be related to octreotide treatment: angina; diarrhoea with dehydration complication; and elevated INR, likely due to interaction with Coumadin. These all resolved to at least grade 1 with discontinuation of octreotide treatment. The most common grade 1 and 2 events related to octreotide treatment were diarrhoea (n = 4), fatigue (n = 3) and flatulence (n = 3). Loss of nocturnal peripheral vision A 62-year-old woman on chronic haemodialysis for end-stage renal disease developed a massive polycystic liver and underwent trial treatment with octreotide [75A]. A test dose of 100 μg ­subcutaneous resulted in diarrhoea, vomiting and abdominal cramps several hours after administration which had disappeared by the following day. Diarrhoea, nausea and vomiting persisted when treatment was reduced to 20 mg and then 10 mg per month of long-acting octreotide. After 3 months of treatment, the patient reported loss of nocturnal peripheral vision that was likely related to vitamin A malabsorption in relation to chronic steatorrhoea, which is a known side effect of octreotide. Diarrhoea, steatorrhoea, visual defects and vitamin A levels concomitantly recovered 2 months after cessation of octreotide treatment. Placebo-controlled trials A randomised trial of long-acting octreotide (30 mg; n = 16) vs placebo (n = 17) for the treatment of symptomatic malignant ascites found that octreotide was not effective in prolonging time to next paracentesis, but did improve abdominal bloating and discomfort, and shortness of breath [76c]. Ten grade 4 adverse events occurred in six patients in the treatment group (abdominal pain, hyperkalaemia, cognitive dysfunction, ­dehydration, neutropenia, fatigue, hypoxia and anaemia) and four grade 4 events occurred in three patients in the placebo group (abdominal pain, fatigue and hepatic failure). Oral versus subcutaneous administration A partly randomised study of oral (20 mg) versus subcutaneous (0.1 mg) octreotide administration in 75 subjects found that the two routes of administration had a similar pharmacokinetic profile, suggesting oral administration may be a viable alternative for persons suffering ongoing adverse injection-site reactions [77C]. Accordingly, 38% of the subcutaneous treatment group reported injection-site reactions to treatment which were obviously not present in the oral treatment group. Abdominal pain was slightly higher in the oral treatment group (15% vs 12%) as was discolouration of faeces (10% vs 4%). Long-term infusion in infants An open-label study of 15 Japanese infants with diazoxide-unresponsive KATPchannel hyperinsulinism found that long-term, continuous, subcutaneous octreotide treatment appeared to be safe and efficacious [78c]. Transient gastrointestinal problems and growth deceleration at higher doses of octreotide were the primary adverse events encountered in the study. Given the small sample size and possibility of serious side

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effects in this population (such as necrotising enterocolitis), larger, well-designed trials are required to provide more conclusive insights into the safety of octreotide treatment in this population.

VASOPRESSIN RECEPTOR ANTAGONISTS [SEDA-34, 713; SEDA-35, 797] Conivaptan Review A review of the literature examining conivaptan treatment of hyponatraemia in neurologic and neurosurgical adult patients identified asymptomatic hypokalaemia and hyperkalaemia, and hypotension as the most common treatment-emergent adverse events [79R]. Open-label trial An open-label trial of intravenous conivaptan in patients with mild or moderate hepatic or renal impairment versus those with normal function (N = 51) found that treatment was generally safe and well tolerated, with injection-site reactions the most commonly reported adverse event [80c].

Tolvaptan Placebo-controlled trials A randomised, placebo-controlled trial of tolvaptan for the treatment of hyponatraemia in patients with cirrhosis (N = 120) found that, overall, adverse events occurred in 92.1% of tolvaptan patients and 82.5% of placebo patients [81C]. Serious treatment-emergent adverse events occurred in 38.1% and 29.8% of the tolvaptan and placebo groups, respectively. Withdrawals due to adverse events were similar for the tolvaptan and placebo group (14.3% and 15.8%, respectively). Adverse events that were, or were trending, towards being observed more frequently in the tolvaptan versus placebo group were gastrointestinal bleeding (10 vs 2%), constipation (9.5 vs 0%), dry mouth (12.7 vs 1%), pyrexia (6.3 vs 0%), thirst (17.5 vs 5.3%) and increased urinary frequency (6.3 vs 0%). A phase III randomised, placebo-controlled trial of 3-year tolvaptan treatment of 1445 patients (18–50 years of age) with autosomal dominant polycystic kidney disease (APKD) found that treatment was effective at slowing the increase in kidney volume and decline in kidney function [82C]. There were fewer APKD-related adverse events (kidney pain, haematuria, urinary tract infection, back pain) in the treatment group but more events related to aquaresis (thirst, polyuria, nocturia and polydipsia) and a greater proportion in the treatment group had elevated liver enzymes. These treatment-related events contributed to a higher discontinuation rate in the treatment group (23% vs 14%) with 15% of discontinuations in the treatment group due to adverse events compared to 5% in the placebo group. A randomised, placebo-controlled trial of oral tolvaptan in healthy Korean men (N = 46) found that the most common treatment-emergent adverse event was thirst (occurring in 40% of the treatment group vs 0% of the placebo group) due to the aquaretic actions of tolvaptan [83C]. Pharmacokinetics A randomised, open-label trial of a single 30-mg dose of tolvaptan in healthy Caucasian (n = 24) and Japanese (n = 24) males found that body weight but not race affected tolvaptan pharmacokinetics [84c]. Another randomised, open-label trial of healthy subjects (N = 24) found that tolvaptan did not alter the pharmacokinetics or pharmacodynamics of warfarin [85c].

Lixivaptan Placebo-controlled trials A phase III randomised, placebo-controlled trial of oral lixivaptan for the treatment of nonhospitalised individuals with euvolemic hyponatraemia (N = 205) found that treatment was effective at increasing serum sodium concentrations [86C]. Adverse events that occurred at least 5% more frequently in the lixivaptan versus placebo group were urinary tract infection (12 vs 4%), polyuria (7 vs 0%) and upper respiratory tract infection (6 vs 0%). Adverse events that occurred at least 5% less frequently in the lixivaptan versus placebo group were headache (8 vs 14%), nausea (7 vs 14%) and dehydration (0 vs 6%). The incidence of serious adverse events with lixivaptan was 18.3% compared to 26.9% with placebo. A phase III randomised, placebo-controlled trial of lixivaptan for the treatment of hospitalised patients (N = 106) with euvolemic hyponatraemia found that treatment was effective at increasing serum sodium concentrations [87C]. Adverse events that occurred at least 5% more frequently in the lixivaptan versus placebo group were constipation (14 vs 8%), dizziness (12 vs 2%), insomnia (12 vs 2%) and asthenia (8 vs 0%). Adverse events that occurred at least 5% less frequently in the lixivaptan versus placebo group were diarrhoea (4 vs 10%), urinary tract infection (4 vs 16%), hypertension (2 vs 10%) and cough (2 vs 10%). The incidence of serious adverse events with lixivaptan was 16% compared to 29% with placebo.

Vasopressin and Analogues [SED-15, 3609; SEDA-33, 915; SEDA-34, 714; SEDA-35, 798]

669

VASOPRESSIN AND ANALOGUES [SED-15, 3609; SEDA-33, 915; SEDA-34, 714; SEDA-35, 798] Desmopressin (N-deamino-8-d-arginine vasopressin, DDAVP) [SED-15, 1076; SEDA-22, 916; SEDA-34, 714; SEDA-35, 798] Venous thrombosis A case study reported the occurrence of venous thrombosis within 1 h after intravenous application of desmopressin to a 76-year-old women with idiopathic diabetes insipidus 5 days after free flap t­ ransfer, highlighting the potential risk of thrombotic incidents when desmopressin is used following microsurgical procedures [88A]. Placebo-controlled trial A randomised trial comparing 25 μg orally disintegrating desmopressin tablet to placebo in the treatment of female patients with nocturia (N = 261, aged 19–87 years) found modest but significant effects of treatment on the number of nocturnal voids per night and mean time to first nocturnal void [89C]. The only adverse event associated with treatment was a reduction in serum sodium to <130 mmol/L in three patients. Sex differences A randomised controlled trial examining sex differences (n = 58 female, n = 54 male) in the efficacy and dose response to oral desmopressin in Japanese patients with nocturia found that the optimal treatment dose was lower in females (∼25 μg) than in males (∼58 μg) [90C], supporting recent studies indicating that female patients are more sensitive to desmopressin [91R]. Tailoring dose according to gender could play an important role in reducing risk of hyponatraemia without affecting efficacy. Reduction of serum sodium levels were the most common adverse events related to treatment, with incidence appearing to increase with the higher doses (one patient in the 10 μg treatment group, three in the 50 μg group and five in the 100 μg group).

Terlipressin [SEDA-33, 916; SEDA-34, 714; SEDA-35, 798] Continuous versus intermittent administration A study randomised 20 patients who underwent a transjugular intrahepatic portosystemic shunt procedure to be treated with either IV bolus infusion of terlipressin (1 mg) followed by continuous infusion (4 mg/24 h) or intravenous bolus injection of terlipressin (2 mg) followed by intermittent injections (1 mg/6 h) [92c]. The continuous administration route more stably reduced portal venous pressure and did so with a lower initial IV dose, which could minimise the risk of adverse drug reactions. Larger studies are required to assess that possibility. Pulmonary oedema A comparative retrospective analysis of 23 patients who received terlipressin for hyponatraemia associated with liver disease versus 11 matched patients who did not receive terlipressin found that terlipressin appeared effective in treating hyponatraemia in liver failure [93c]. However, terlipressin use was associated with greater incidence of adverse events. The predominant side effect of treatment was pulmonary oedema (occurring in 15 patients), possibly related to terlipressin’s action as a vasoconstrictor. Cardiac arrest A case study reported a 47-year-old woman with normal QT interval, baseline electrolytes and no family history of long QT syndrome or sudden cardiac death having cardiac arrest with rhythm being torsades de pointes 24 h after initiation of terlipressin for treatment of gastrointestinal bleeding [94A]. This was associated with prolonged QT interval. Clinical trials and postmarketing reports have shown that QT prolongation and torsades de pointes have occurred with terlipressin but usually when patients had predisposing factors. This case study indicates that terlipressin-associated ventricular arrhythmias may occur even in patients without any apparent predisposing factors and thus all patients undergoing terlipressin treatment should be monitored for this potentially lethal side effect. Skin ischaemia A case study reported a 47-year-old undergoing terlipressin therapy (1 mg, six times a day) developing skin ischaemia on the third day of treatment [95A]. Injections of terlipressin were ceased and lesions promptly began to regress, with a complete recovery by 2 weeks post incident. Given the regress of symptoms upon cessation of treatment, the diagnosis was terlipressin-induced vasculopathy leading to skin ischaemia.

Vasopressin [SED-15, 3609; SEDA-34, 715; SEDA-35, 798] Infusion in neonates following cardiac surgery A retrospective study of 19 neonates who received low-dose vasopressin infusion in the operating room following complex cardiac surgery versus 18 neonates who did not receive early vasopressin infusion following surgery found that low-dose vasopressin infusion was associated with decreased fluid resuscitation and catecholamine requirements in the 24 h following surgery [96c]. The low-dose vasopressin infusion did not detrimentally impact measured haemodynamic or oxygen transport measures and no serious adverse events were associated with treatment. Larger, well-designed studies are required to properly confirm the efficacy and safety of low-dose vasopressin infusion in this population.

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Examination of data from neonates who had undergone complex cardiac surgery either with (n = 17) or without (n = 17) the use of vasopressin found that vasopressin treatment was associated with higher urea and creatinine levels, longer period of peritoneal dialysis, reduced platelet counts and delayed recovery of lactate concentration [97c]. The authors suggest that vasopressin infusion should only be used in catecholamine-refractory shock. The potentially dangerous outcomes reported in this study should be assessed carefully in future trials. Transiently increased blood pressure A prospective, pilot, matched control, clinical trial of vasopressin (0.8 U/kg; n = 10 AVP treatment, n = 20 control) as a second vasopressor following epinephrine for the treatment of paediatric cardiopulmonary arrest refractory to initial epinephrine dosing found no adverse events directly attributable to vasopressin [98c]. Vasopressin-treated patients had significantly higher 24-h postcardiac arrest hepatic enzyme levels, which returned to normal levels 48 h following cardiac arrest. No vasopressin patients reported allergic reaction, gastrointestinal bleeding, skin necrosis or arrhythmia following vasopressin administration. Half (50%) of AVP-treated patients had mildly increased blood pressure following vasopressin administration. The Data Safety Monitoring Board’s only concern was the possibility that vasopressin may improve 24-h survival but increase the risk of a poor neurologic outcome. Long-term follow-up was recommended in future studies to more definitively assess neurologic outcomes. Hyponatraemia In a retrospective, chart-review study of 29 paediatric patients who received arginine vasopressin in the first 2 days following cardiothoracic surgery compared to 47 paediatric patients who did not receive postoperative vasopressin, it was found that hyponatraemia occurred in nearly half of the infants and children receiving vasopressin therapy [99c]. This highlights the importance of careful monitoring of serum sodium levels in children undergoing vasopressin treatment and suggests preventative measures such as provision of less free water should be considered. Placebo-controlled trial A randomised, placebo-controlled trial of vasopressin + epinephrine versus placebo + epinephrine in 268 patients with cardiac arrest found that combined treatment improved survival to hospital discharge with favourable neurological outcomes. The rates of adverse events were similar in the two groups [100C].

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