Ulipristal Acetate: A Review in Symptomatic Uterine Fibroids.

Oral ulipristal acetate (Esmya®; Fibristal®), a synthetic selective progesterone receptor modulator, is the first selective progesterone modulator to be approved for the treatment of uterine fibroids. It was initially approved for the preoperative treatment of moderate to severe uterine fibroid symptoms in women of reproductive age. Recently, the indication was extended in the EU to include the intermittent treatment of moderate to severe uterine fibroid symptoms. This narrative review summarizes pharmacological, efficacy and tolerability data relevant to the preoperative and intermittent use of ulipristal acetate in patients with symptomatic uterine fibroids. Ulipristal acetate is an effective and generally well tolerated treatment for patients with symptomatic uterine fibroids, both as preoperative, single-course treatment and as intermittent, longer-term treatment. It is noninferior in efficacy to intramuscular leuprolide acetate, as a preoperative treatment, and is associated with a lower rate of hot flashes, a common adverse event with gonadotropin-releasing hormone analogues. Thus, ulipristal acetate is an effective option for both preoperative and intermittent treatment of moderate to severe, symptomatic uterine fibroids in women of reproductive age.

Ixazomib: A Review in Relapsed and/or Refractory Multiple Myeloma.

The oral proteasome inhibitor ixazomib (Ninlaro®) is approved in the USA, EU and Japan in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. In adults with relapsed and/or refractory MM who had received one to three prior therapies, progression-free survival (PFS) was significantly prolonged in patients who received the ixazomib- versus placebo-based triple therapy in the pivotal, global TOURMALINE-MM1 trial and its regional expansion (China continuation study). A significantly longer time to progression and favourable hazard ratios for PFS were observed across all prespecified subgroups, including patients with high cytogenetic risk. Overall response was achieved in a significantly higher proportion of patients receiving ixazomib- than placebo-based treatment. Ixazomib had a manageable tolerability profile in patients with MM. Ixazomib is the first orally-administered proteasome inhibitor approved for patients with MM, and in combination with lenalidomide and dexamethasone represents an important new option for use in patients with relapsed and/or refractory MM who have previously received at least one prior therapy.

Cariprazine: A Review in Schizophrenia.

Cariprazine (Vraylar™) is a dopamine D3-preferring D2/D3 receptor partial agonist indicated for the treatment of patients with schizophrenia. This narrative review summarizes pharmacological, efficacy and tolerability data relevant to the use of cariprazine in patients with this disorder. In 6-week, phase IIb and III trials in patients with schizophrenia, cariprazine was significantly more efficacious than placebo in improving schizophrenia symptoms, including improvements in Positive and Negative Syndrome Scale (PANSS) total scores. It was associated with a significantly longer time to relapse than placebo in a long-term, phase III, relapse-prevention study. Cariprazine was also significantly more efficacious than risperidone in improving PANSS Factor Score for Negative Symptoms in a phase III trial in patients with predominantly negative symptoms of schizophrenia, a typically difficult to treat group of patients. Cariprazine was generally well tolerated in clinical trials, with most adverse events being of mild to moderate severity, and metabolic changes observed were considered generally not clinically significant. Cariprazine is a useful addition to the treatment options for schizophrenia, and may be of particular use in patients with predominantly negative symptoms.

Saxagliptin/Dapagliflozin: A Review in Type 2 Diabetes Mellitus.

Saxagliptin/dapagliflozin fixed-dose combination tablets (Qtern®) are indicated in the EU for the improvement of glycaemic control in adults with type 2 diabetes mellitus (T2DM), either when treatment with metformin and/or a sulfonylurea plus a monocomponent of saxagliptin/dapagliflozin provides inadequate glycaemic control, or when the patient is already being treated with the free combination of saxagliptin + dapagliflozin. This narrative review summarizes pharmacological, efficacy and tolerability data relevant to the use of saxagliptin/dapagliflozin in this indication. The agents have complementary mechanisms of action, and saxagliptin/dapagliflozin fixed-dose combination tablets are bioequivalent to free combination of saxagliptin + dapagliflozin. In three phase III trials, saxagliptin + dapagliflozin + metformin was more effective at providing glycaemic control than saxagliptin + metformin or dapagliflozin + metformin in previously treated patients with T2DM and inadequate glycaemic control on metformin monotherapy or metformin plus one of the monocomponents. The combination is associated with decreased bodyweight and a low risk of hypoglycaemia. As the first dipeptidyl peptidase-4 (DPP-4) inhibitor/sodium-glucose co-transporter (SGLT2) inhibitor fixed-dose combination available in the EU for glycaemic control in patients with T2DM, saxagliptin/dapagliflozin is a useful new option in this setting.

Single-Dose Dalbavancin: A Review in Acute Bacterial Skin and Skin Structure Infections.

Intravenous dalbavancin (Dalvance®, Xydalba®), first approved as a two-dose regimen for the treatment of acute bacterial skin and skin structure infections (ABSSSI), has now been additionally approved as a single-dose regimen. This narrative review discusses the pharmacological properties of intravenous dalbavancin and its clinical efficacy and tolerability as a single-dose regimen in the treatment of adult patients with ABSSSI. Single-dose dalbavancin is an effective and generally well tolerated treatment option for adults with ABSSSI, with noninferior efficacy to the two-dose dalbavancin regimen with regard to early clinical response (at 48-72 h) and low rates of adverse events. Clinical success rates at days 14 and 28 also did not significantly differ between the single- and two-dose dalbavancin regimens; neither did clinical success rates at day 14 when analysed by baseline pathogen. It has a broad spectrum of activity against common ABSSSI-related pathogens, and a favourable pharmacokinetic profile allowing for the convenience of single-dose administration. Thus, dalbavancin presents a promising alternative to conventional antibacterials for the treatment of ABSSSI in adult patients.

Oxycodone DETERx® ER Capsules: A Review in Severe, Chronic Pain.

Oxycodone DETERx ® extended-release (ER) capsules (Xtampza® ER), an abuse-deterrent formulation of oxycodone as the myristate salt, are approved in the USA for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. This narrative review discusses the clinical efficacy and tolerability of the oxycodone DETERx ® ER capsule formulation in the management of severe pain, and provides an overview of pharmacokinetics, abuse-deterrent properties and alternative administration options. The microsphere-in-capsule DETERx ® drug delivery platform allows administration via sprinkle-dosing or enteral tubes. The physicochemical properties of the formulation make it difficult to manipulate and its ER pharmacokinetic profile is retained after crushing or chewing. Clinical abuse-potential studies suggest these properties may translate to reduced intranasal abuse, with implications for abuse via the oral route less certain. The efficacy of oxycodone DETERx ® ER in the management of moderate to severe, chronic pain was demonstrated in a well designed, phase III trial, in which it was more effective than placebo at reducing pain intensity. The formulation was generally well tolerated in this trial; the most common treatment-emergent adverse events were nausea and constipation. As an opioid, oxycodone DETERx ® ER carries risks of addiction, abuse and misuse. Post-marketing epidemiological studies will be necessary in determining the impact of oxycodone DETERx ® on oxycodone abuse liability. Nevertheless, oxycodone DETERx ® ER is a useful treatment option for patients with severe, chronic pain, particularly when comorbid dysphagia or difficulty swallowing is a concern.

Apixaban: A Review in Venous Thromboembolism.

Apixaban (Eliquis®) is an oral, direct factor Xa inhibitor that is available for use in the treatment and secondary prevention of venous thromboembolism (VTE). Like other direct oral anticoagulants (DOACs), apixaban has generally predictable pharmacological properties and does not require routine anticoagulation monitoring. In large phase III trials, oral apixaban was noninferior to subcutaneous enoxaparin sodium overlapped with and followed by oral warfarin (enoxaparin/warfarin) in the treatment of adults with acute VTE over 6 months with regard to the incidence of recurrent VTE or VTE-related death (AMPLIFY), and was significantly more effective than placebo in the prevention of recurrent VTE or all-cause mortality over 12 months in patients who had completed 6-12 months' anticoagulation treatment for VTE (AMPLIFY-EXT). Apixaban was generally well tolerated in these trials; the risks of major bleeding and the composite endpoint of major or clinically relevant nonmajor (CRNM) bleeding with apixaban were significantly lower than enoxaparin/warfarin in AMPLIFY and not significantly different from that of placebo in AMPLIFY-EXT. Similarly, in Japanese adults with acute VTE (AMPLIFY-J), apixaban was associated with a significantly lower risk of major or CRNM bleeding than unfractionated heparin plus warfarin, and no cases of recurrent VTE or VTE-related death over 24 weeks. Thus, apixaban is useful therapeutic alternative for the management of adults with VTE.

Adalimumab: A Review in Hidradenitis Suppurativa.

Subcutaneous adalimumab (Humira®) is a tumour necrosis factor-α blocker that is the only approved agent for the treatment of moderate to severe hidradenitis suppurativa (HS) in several countries worldwide. This article reviews the clinical efficacy and safety of subcutaneous adalimumab in patients with moderate to severe HS. In clinical trials (PIONEER I and II), a greater proportion of adalimumab than placebo recipients reached HS clinical response (HiSCR) at week 12. The main secondary endpoints, such as the proportion of patients with an abscess and inflammatory nodule count of ≤2 at week 12, were significantly greater with adalimumab than with placebo in PIONEER II, but not in PIONEER I. In addition, adalimumab showed the potential to reduce the high health-related quality of life burden of HS and increase patient satisfaction. HiSCR rates were generally maintained in the longer term, and the safety profile of adalimumab in patients with moderate to severe HS was consistent with the known safety profile of the drug for other indications, with no new emerging safety signals. Adalimumab is an effective and generally well tolerated treatment for patients with moderate to severe HS, and is the first agent approved for this difficult-to-treat disease.

Talimogene Laherparepvec: A Review in Unresectable Metastatic Melanoma.

Talimogene laherparepvec (Imlygic™) is a first-in-class oncolytic viral immunotherapy derived from herpes simplex virus type 1, which has been genetically modified to increase tumour selectivity and stimulate antitumour immune response. This article reviews the pharmacological properties of intralesional talimogene laherparepvec and its clinical efficacy and tolerability in patients with unresectable metastatic melanoma. In the phase III OPTiM trial, talimogene laherparepvec was more effective than subcutaneous human granulocyte-macrophage colony-stimulating factor (GM-CSF), both in patients with stage IIIB-IV melanoma [intention-to-treat (ITT) population] and in those with stage IIIB-IVM1a disease (in an exploratory subgroup analysis). Durable response rate (DRR) was significantly higher with talimogene laherparepvec in the ITT population; beneficial results in DRR were also observed in talimogene laherparepvec recipients in patients with stage IIIB-IVM1a disease. Talimogene laherparepvec was generally well tolerated in clinical trials. In conclusion, talimogene laherparepvec is a novel, effective and well tolerated option for the treatment of patients with unresectable metastatic melanoma.

Fosaprepitant Dimeglumine: A Review in the Prevention of Nausea and Vomiting Associated with Chemotherapy.

Intravenous fosaprepitant dimeglumine (Emend(®) for injection, IVEmend(®); henceforth referred to as fosaprepitant) is a prodrug of and is rapidly converted to the antiemetic aprepitant, and is approved in several countries worldwide (as part of an antiemetic regimen) for the prevention of nausea and vomiting associated with highly and moderately emetogenic chemotherapy (HEC and MEC). This narrative review discusses the pharmacological properties of intravenous fosaprepitant and its clinical efficacy and tolerability in the prevention of nausea and vomiting associated with HEC and MEC. In large, randomized phase III clinical trials, a single intravenous dose of fosaprepitant 150 mg was an effective and generally well tolerated addition to an antiemetic regimen that included dexamethasone and a serotonin 5-HT3 receptor antagonist in adult cancer patients undergoing treatment with HEC or MEC. It was also noninferior to an oral aprepitant-based regimen in adult cancer patients undergoing HEC treatment. The tolerability profile of a fosaprepitant-based regimen was typical of that in patients receiving emetogenic chemotherapy, and adverse events were generally consistent with those observed with an aprepitant-based regimen. Fosaprepitant provides a useful addition to antiemetic therapy regimens.

Loxoprofen: A Review in Pain and Inflammation.

Loxoprofen (Loxonin(®), Loxonin(®) Pap, Loxonin(®) Tape) is a prodrug-type NSAID that is available in several formulations, including 60 mg tablets, 100 mg hydrogel patches and 50 or 100 mg tape. In active comparator-controlled trials, oral loxoprofen therapy (ranging from 2 days to 6 weeks' duration depending on the pain type) provided analgesic efficacy that generally did not significantly differ from that of celecoxib for postoperative pain or frozen shoulder, ibuprofen for knee osteoarthritis or naproxen for lumbar pain. In double-blind, double-dummy, multicentre trials, loxoprofen hydrogel patches were noninferior to oral loxoprofen with regard to rates of final overall symptomatic improvement over 1-4 weeks in patients with knee osteoarthritis, myalgia or trauma-induced swelling and pain. Loxoprofen hydrogel patches were also noninferior to other commercially available patches (ketoprofen and indometacin) over 2 or 4 weeks in patients with knee osteoarthritis or myalgia in open-label studies. Oral and topical loxoprofen were generally well tolerated in clinical trials. Thus, loxoprofen is a useful analgesic option for patients with pain and inflammation, with topical loxoprofen potentially reducing the risk of gastrointestinal, cardiovascular and renal complications associated with oral NSAID use.

Rotigotine Transdermal Patch: A Review in Restless Legs Syndrome.

Rotigotine transdermal patch (Leganto(®), Neupro(®)) is indicated for the treatment of restless legs syndrome (RLS); this article reviews the pharmacological properties of rotigotine transdermal patch and its clinical efficacy and tolerability in patients with RLS. The transdermal patch allows for a continuous, stable release of rotigotine (avoiding first-pass metabolism), which in turn leads to continuous receptor stimulation, believed to closely mimic physiological striatal dopamine receptor function. In short-term and 6-month studies, especially at the higher dosages of 2 and 3 mg/24 h, rotigotine transdermal patch was generally associated with a significantly greater improvement in IRLS total score and CGI-S total score than placebo, and rotigotine recipients were generally more likely to respond to treatment and enter remission. In noncomparative extension studies, efficacy was sustained for ≤5 years. Rotigotine transdermal patch is generally well tolerated, and appears to have a tolerability profile that is similar to that of other non-ergolinic dopamine-receptor agonists. The most common adverse events in clinical trials included application-site reactions, nausea, headache and asthenic conditions. The drug has a relatively low risk of clinically significant augmentation of restless legs syndrome symptoms. In conclusion, rotigotine transdermal patch offers continuous administration of the drug in a daily treatment, and is a useful treatment option in patients with RLS.

Eltrombopag: A Review in Paediatric Chronic Immune Thrombocytopenia.

Eltrombopag (Promacta(®); Revolade(®)) is an orally active thrombopoietin receptor agonist recently approved in the USA and the EU for use in paediatric patients aged ≥1 year with chronic immune thrombocytopenia (ITP) who have had an insufficient response or are refractory to other ITP treatments (e.g. corticosteroids, immunoglobulins or splenectomy). The efficacy of 7 or 13 weeks' therapy with oral eltrombopag (up to 75 mg/day) was compared with that of placebo in patients aged 1-17 years with previously treated chronic ITP in randomized, double-blind, multicentre phase II and III trials (PETIT and PETIT-2). In these trials, the platelet response rate (primary endpoint of PETIT) and the sustained platelet response rate (primary endpoint of PETIT-2) were significantly higher with eltrombopag than with placebo. A clinical benefit was shown by a reduction in the need for rescue therapy with eltrombopag versus placebo in both trials and a reduction of clinically significant bleeding in PETIT. During longer-term therapy (open-label treatment period for ≥24 weeks), eltrombopag maintained platelet counts above 50 × 10(9)/L in the majority of patients and approximately one-half of patients were able to reduce or discontinue concurrent ITP drugs. Eltrombopag was generally well tolerated. Current evidence suggests that eltrombopag is a valuable addition to the limited treatment options available for the management of chronic ITP in paediatric patients with an inadequate response to first-line therapies.

Brexpiprazole: A Review in Schizophrenia.

Oral brexpiprazole (Rexulti(®)) is a partial dopamine D2 agonist, which also has activity at several other receptors. This article reviews the pharmacological properties of brexpiprazole and its clinical efficacy and tolerability in patients with schizophrenia; its use in patients with major depressive disorder is beyond the scope of this review. Brexpiprazole 2-4 mg/day was generally effective in short-term, phase III studies at improving Positive and Negative Symptom Scale scores and other schizophrenia symptoms in patients with acute schizophrenia. Moreover, maintenance treatment with brexpiprazole 1-4 mg/day was associated with a significantly longer time to exacerbation of disease or impending relapse than placebo. The drug was well tolerated in clinical trials, with most serious adverse events in the short term being associated with the underlying disorder. Overall, oral brexpiprazole is a useful treatment option for the treatment of patients with schizophrenia.

Fentanyl Buccal Soluble Film: A Review in Breakthrough Cancer Pain.

Fentanyl buccal soluble film (Onsolis(®), Breakyl(®), Painkyl™) comprises two layers: a mucoadhesive layer containing the active drug, and an inactive layer with the aim of preventing the diffusion of fentanyl into the oral cavity. It is approved in several countries worldwide, including the USA and those of the EU, for the management of breakthrough cancer pain in opioid-tolerant, adult patients with cancer. This article reviews the pharmacological properties of fentanyl buccal soluble film and its clinical efficacy and tolerability in these patients. Fentanyl buccal soluble film provides an additional option for transmucosal delivery of fentanyl, with approximately half of the dose undergoing an initial, rapid absorption via the buccal mucosa (accounting for its high bioavailability). In clinical trials, fentanyl buccal soluble film was associated with significant improvements in pain intensity scores versus placebo and was generally well tolerated. The most common adverse events were typical opioid-associated adverse events, such as nausea and vomiting. Fentanyl buccal soluble film is a useful option for the treatment of breakthrough cancer pain in opioid-tolerant patients.

Afamelanotide: A Review in Erythropoietic Protoporphyria.

Afamelanotide (SCENESSE(®)) is a synthetic α-melanocyte stimulating hormone analogue and first-in-class melanocortin-1 receptor agonist that is approved in the EU for the prevention of phototoxicity in adults with erythropoietic protoporphyria (EPP). It is administered subcutaneously as a biodegradable, controlled-release implant containing 16 mg of afamelanotide. This article reviews the clinical efficacy and tolerability of afamelanotide in EPP and summarizes its pharmacological properties. In the phase III trial, CUV039, afamelanotide treatment improved light tolerance in patients with EPP. Compared with placebo, afamelanotide treatment enabled patients to spend more time in direct sunlight without pain and increased the time to the appearance of the first symptoms of phototoxicity provoked by a standardized light source. Afamelanotide was generally well tolerated in this trial, with no drug-related serious adverse events reported. Commonly occurring adverse reactions included headache and implant-site reactions. Efficacy and safety data from earlier phase III trials are consistent with those from the CUV039 trial. Afamelanotide, approved in the EU for the prevention of EPP phototoxicity, represents a useful addition to the management of the disorder.

Necitumumab: First Global Approval.

Eli Lilly is developing necitumumab (Portrazza™), an intravenously administered fully human IgG monoclonal antibody directed against the epidermal growth factor receptor (EGFR), which is expressed in a variety of solid tumours and has been implicated in promoting oncogenesis and tumour progression. Necitumumab is approved as a part of combination therapy (with gemcitabine and cisplatin) in the USA for the first-line treatment of metastatic squamous non-small cell lung cancer (NSCLC), and regulatory submissions have been made in the EU for this same indication. Necitumumab was derived from the proprietary phage display library of Dyax Corp, and originated with ImClone Systems, which was acquired by Eli Lilly in November 2008. Necitumumab was also under phase II development for colorectal cancer in Belgium and Spain; however, no recent development has been reported for this indication. This article summarizes the milestones in the development of necitumumab leading to this first approval for the first-line treatment of metastatic squamous NSCLC, in combination with gemcitabine and cisplatin.

Prucalopride: A Review in Chronic Idiopathic Constipation.

Prucalopride (Resolor®), a highly selective serotonin 5-HT4 receptor agonist, is indicated in the European Economic Area for the treatment of adults with chronic idiopathic constipation (CIC) in whom laxatives have failed to provide adequate relief. This article reviews the pharmacological properties of prucalopride and its clinical efficacy and tolerability in patients with CIC. In five well-designed, 12-week trials in patients with CIC, oral prucalopride 2 mg/day was significantly more effective than placebo at improving bowel function, including the number of bowel movements and a range of other constipation symptoms, as well as health-related quality of life and patient satisfaction; however, no significant differences in bowel function measures were observed between prucalopride and placebo in a 24-week trial. Oral PEG-3350 + electrolytes reconstituted powder was found to be noninferior but not superior to prucalopride according to primary endpoint data from a 4-week, controlled-environment trial. Prucalopride was generally well tolerated in clinical trials; the most common adverse events were headache, diarrhoea, nausea and abdominal pain. No cardiovascular safety issues have arisen with prucalopride treatment. Although further long-term and comparative data would be beneficial, prucalopride provides an additional treatment option for patients with CIC.

Cobimetinib: First Global Approval.

Genentech (a subsidiary of Roche) and Exelixis are developing cobimetinib, an orally available small molecule, for the treatment of various cancers, including malignant melanoma and breast cancer. Cobimetinib inhibits the MEK (mitogen-activated protein kinase) component of the MAPK/ERK signalling pathway, which is frequently over-activated in human tumours. The product has been approved in Switzerland in combination with vemurafenib for the treatment of patients with unresectable or metastatic BRAF V600 mutation-positive melanoma, and is under regulatory review for the same indication in several countries, including the USA and the EU. This article summarizes the milestones in the development of cobimetinib leading to this first approval for unresectable or metastatic BRAF V600 mutation-positive melanoma melanoma.

Roflumilast: A Review in COPD.

Roflumilast (Daliresp®, Daxas®) is a selective phosphodiesterase 4 (PDE4) inhibitor that decreases systemic and pulmonary inflammation and improves disease symptoms in patients with severe chronic obstructive pulmonary disease (COPD). This article reviews the pharmacological properties of roflumilast and its clinical efficacy and tolerability in patients with COPD. Roflumilast is an effective treatment in patients with moderate to severe COPD; it improves lung function and is generally associated with a lower risk of exacerbation, particularly in patients with more severe disease and/or chronic bronchitis, cough and sputum. It is generally well tolerated; the most common adverse event was diarrhoea. While associated with an increased risk of psychiatric adverse events and weight loss, roflumilast is not associated with an increased risk of respiratory disease and infection, and may decrease the risk of cardiovascular adverse events. Roflumilast is a useful addition to the treatment options for patients with COPD.