Fluocinolone Acetonide Intravitreal Implant for Treating Recurrent Non-infectious Uveitis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited Alimera Sciences, the company manufacturing fluocinolone acetonide intravitreal implant (FAc) 0.19 mg (tradename ILUVIEN®), to submit evidence on the clinical and cost-effectiveness of FAc for treating recurrent non-infectious uveitis. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre + , was commissioned to act as the independent Evidence Review Group (ERG). This paper contains a summary of the clinical and cost-effectiveness evidence submitted by the company, the ERG's critique on the submitted evidence, and the guidance issued by the NICE Appraisal Committee (AC). The company submission (CS) was mainly informed by the PSV-FAI-001 trial in which FAc was compared with (limited) current practice [(L)CP], which was not considered to be representative of UK clinical practice by the ERG. There was no comparison of FAc to any treatment listed in the final scope, and especially to the dexamethasone intravitreal implant (dexamethasone), which was considered to be a relevant comparator by the AC. The primary outcome of the PSV-FAI-001 was recurrence of uveitis in the treated eye. Most of the events for the primary outcome were imputed during the PSV-FAI-001 trial, which probably led to an overestimation of the number of recurrences of disease, and a biased estimate of the relative effectiveness of FAc versus (L)CP. Finally, the place of FAc in the treatment pathway was not clearly defined by the company. Substantial uncertainty surrounded the cost-effectiveness results due to the shortcomings of the clinical evidence. Additionally, the quality of life of patients was not measured during the PSV-FAI-001 trial and long-term effectiveness data of FAc were lacking. The ERG adjusted several issues identified in the CS and added dexamethasone as a comparator in the decision analytic model. The ERG presented multiple analyses as base-cases because several elements of the assessment remained uncertain. The fully incremental ERG results ranged from dexamethasone (extendedly) dominating FAc (when assuming a hazard ratio of 1 or 0.7 for dexamethasone versus FAc) to an incremental cost-effectiveness ratio (ICER) of £30,153 per quality-adjusted life-year (QALY) gained for FAc versus (L)CP [when assuming a hazard ratio of 0.456 for dexamethasone versus (L)CP]. The ICER of FAc versus (L)CP ranged from £12,325 to £30,153 per QALY gained. After a second AC meeting where alternative company scenarios comparing FAc with dexamethasone were considered by the AC, the AC concluded that "the results of the company's analyses ranged from the fluocinolone acetonide implant being dominant (that is, it was more effective and costs less), to an ICER of £29,461 per QALY gained, and most of the ICERs were below £20,000 per QALY gained". Therefore, the AC recommended FAc as a cost-effective use of National Health Service (NHS) resources for treating recurrent non-infectious uveitis affecting the posterior segment of the eye in the final TA590 guidance (published July 2019).

Efficacy and Safety of Ciprofloxacin Plus Fluocinolone in Otitis Media With Tympanostomy Tubes in Pediatric Patients: A Randomized Clinical Trial.

Importance: Acute otitis media with tympanostomy tubes (AOMT) in children commonly presents with otorrhea and negatively affects their daily activities. Objective: To evaluate the efficacy and safety of topical ciprofloxacin, 0.3%, plus fluocinolone acetonide, 0.025%, otic solution relative to ciprofloxacin, 0.3%, otic solution alone and fluocinolone acetonide, 0.025%, otic solution alone in the treatment of AOMT in children. Design, Setting, and Participants: Two twin multicenter, randomized, double-blind clinical trials with identical designs were conducted from June 24, 2011, through June 23, 2014, at ear, nose, and throat pediatric practices, general practices, hospitals, and clinical research centers. The study population comprised 662 children (331 in each trial) with AOMT in at least 1 ear who presented with moderate or severe purulent otorrhea for 3 weeks or less. Data analyses were performed on an intention-to-treat basis. Interventions: Patients were randomly assigned to receive ciprofloxacin plus fluocinolone, ciprofloxacin alone, or fluocinolone alone twice daily for 7 days and were evaluated on days 1 (baseline), 3 to 5 (undergoing therapy), 8 to 10 (end of therapy), and 18 to 22 (test of cure). Main Outcomes and Measures: The primary efficacy measure was time to cessation of otorrhea. The principal secondary end point was sustained microbiological cure, defined as eradication or presumed eradication at end-of-therapy and test-of-cure visits. Results: A total of 662 children participating in the 2 studies were randomized to receive ciprofloxacin plus fluocinolone (n = 223), ciprofloxacin alone (n = 221), or fluocinolone alone (n = 218). The median age was 2.5 years (range, 0.6-12.7 years). The median time to cessation of otorrhea was 4.23 days (95% CI, 3.65-4.95 days) in patients receiving ciprofloxacin plus fluocinolone compared with 6.95 days (95% CI, 5.66-8.20 days) in those receiving ciprofloxacin and not estimable findings in those receiving fluocinolone alone (P < .001). The clinical cure rate at the test-of-cure visit was 80.6% in the ciprofloxacin plus fluocinolone group, 67.4% in the ciprofloxacin group (difference, 13.2%; 95% CI, 5.0%-21.4%; P = .002), and 47.6% in the fluocinolone group (difference, 33.0%; 95% CI, 24.0%-42.0%; P < .001). The sustained microbiological cure rate was 79.7% in the ciprofloxacin plus fluocinolone group vs 67.7% in the ciprofloxacin group (difference, 12.0%; 95% CI, 0.8%-23.0%; P = .04) and 37.6% in the fluocinolone group (difference, 42.1%; 95% CI, 29.3%-54.8%; P < .001). Only 7 (3.1%) of the patients receiving ciprofloxacin plus fluocinolone, 8 (3.6%) of the patients receiving ciprofloxacin, and 10 (4.7%) of the patients receiving fluocinolone presented with adverse events related to study medication. Conclusions and Relevance: The combination of ciprofloxacin plus fluocinolone is more effective than treatment with ciprofloxacin or fluocinolone alone for AOMT, and it is safe and well tolerated in children. Trial Registration: clinicaltrials.gov Identifiers: NCT01395966 and NCT01404611.

Triple combination as adjuvant to cryotherapy in the treatment of solar lentigines: investigator-blinded, randomized clinical trial.

BACKGROUND: Post-inflammatory hyperpigmentation is a frequent concern when treating solar lentigines. OBJECTIVES: To assess the safety and efficacy of a triple combination cream with fluocinolone acetonide 0.01%, hydroquinone 4% and tretinoin 0.05% as adjuvant to cryotherapy in the treatment of solar lentigines in hands dorsum, and in the prevention of post-inflammatory hyperpigmentation after cryotherapy. METHODS: This prospective, randomized, controlled, investigator-blinded, single-centre study enrolled 50 patients. Twenty-five patients received a 2-week daily triple combination cream plus sunscreen pre-treatment and 25 received sunscreen alone. After that, cryotherapy was performed in all patients followed by a 3-week recovery period. After this period, patients received the same initial treatment and were followed up for 8 weeks. Melanin and erythema levels of a target and a control lentigo were objectively measured using a narrowband reflectance spectrophotometer. Lentigines count, colour homogeneity and global improvement were also assessed. RESULTS: The number of solar lentigines reduced in the first 2 weeks only in patients who used the triple combination 25 ± 7 vs. 22 ± 8 (P < 0.0001), and reduced at the end of the study for both groups (P < 0.0001). The melanin levels also reduced in the first 2 weeks only in patients who used the triple combination 297 ± 69 vs. 273 ± 66 (P < 0.0001) and reduced at the end of the study for both groups (P < 0.0001). Erythema and residual blisters from cryotherapy were the reported adverse reactions. CONCLUSION: Triple combination cream can be used to enhance the resolution of solar lentigines, and to significantly reduce melanin levels and lentigines count, improving treatment results. It was well-tolerated and did not increase the occurrence of neither erythema nor other side-effects after the cryotherapy.

Carbamazepine-induced DRESS syndrome in a child: rapid response to pulsed corticosteroids.

DRESS syndrome is an idiosyncratic reaction to drugs, which can occur in both adults and children. To date there is no agreed upon criteria for its diagnosis; there is even less consensus on its management. We report the case of a 14- year-old boy with carbamazepine induced DRESS syndrome, predominantly involving the liver. He responded rapidly to high dose pulsed intravenous corticosteroids.

Single-session intense pulsed light combined with stable fixed-dose triple combination topical therapy for the treatment of refractory melasma.

The effectiveness of intense pulsed light (IPL) has been reported in adults with melasma, but there is little information about IPL with triple combination topical therapy (TC) and refractory melasma. Sixty-two patients with totally or partially refractory melasma were enrolled in this randomized open-label study. Thirty-one patients were treated with IPL in a single session, bleaching agents and broad-spectrum sunscreens. Thirty-one patients were in the control group, receiving only bleaching agents and broad-spectrum sunscreens. The Melasma Area and Severity Index (MASI) and the investigator's global assessment using a seven-point scale were used to determine the impact and effectiveness of the treatment. The IPL group results based on MASI showed a 49.4% reduction (from 17.6 to 8.9; p < 0.001) after six months and a 44.9% reduction after 12 months (from 17.6 to 9.7; p < 0.001). The investigator's global assessment showed that the difference in the improvement rate between the IPL group and control group was significant (p = 0.002), with a better response in the IPL group. Single session IPL combined with stable fixed-dose triple combination treatment is a safe and effective treatment for refractory mixed and dermal melasma.

Retisert (Bausch & Lomb/Control Delivery Systems).

Retisert (Envision TD), a sustained release intraocular implant containing fluocinolone acetonide, has been developed and launched in the US by Bausch & Lomb and Control Delivery Systems for the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye.

Flunisolide HFA for the treatment of asthma: an old friend reformulated.

The environmental mandate to eliminate the production of ozone-depleting products including chlorofluorocarbon (CFC) propellants has encouraged much needed research into improving modes of delivery of inhaled corticosteroids and enhancing drug deposition. Consequently, flunisolide CFC, an inhaled corticosteroid with a proven track record in the treatment of asthma, has been reformulated using a hydrofluoroalkane (HFA) as a propellant and is now awaiting FDA approval. Flunisolide HFA is a solution aerosol, unlike flunisolide CFC which is a suspension aerosol. As a solution aerosol, flunisolide HFA has a smaller mean particle size than flunisolide CFC. In addition, the built-in spacer included in the flunisolide HFA inhaler acts to reduce ex-actuator particle size; the smaller particle size of flunisolide HFA results in an improved deposition profile. Flunisolide HFA has substantially more lung deposition and much less oropharyngeal deposition than flunisolide CFC. Limited information is currently available on the clinical performance of flunisolide HFA. A single dose-response study has been performed in adults and in children comparing multiple doses of flunisolide HFA and flunisolide CFC. These studies indicate that flunisolide HFA is effective in controlling asthma. No unusual safety concerns have been noted, although further studies are needed to determine the long-term systemic effects of flunisolide HFA.

A comparative study of punch grafting followed by topical corticosteroid versus punch grafting followed by PUVA therapy in stable vitiligo.

BACKGROUND: Punch grafting followed by PUVA is an established therapy for stable vitiligo, but punch grafting followed by topical corticosteroid has never been evaluated. OBJECTIVE: The aim of this study was to evaluate the efficacy of topical corticosteroid in perigraft pigmentation and to compare it with perigraft pigmentation after PUVA in patients with stable vitiligo. METHODS: Fifty patients with stable vitiligo of various clinical types were subjected to punch grafting. In a randomized case study, these patients were divided into two groups: One group received post punch-grafting PUVA (group I) and the other group post punch-grafting topical application of fluocinolone acetonide 0.1% (group II). During the follow-up period of 6 months, six patients were lost to follow-up, and two patients were excluded from the study; 42 patients were evaluated for pigment spread and side effects. RESULTS: In group I, the average pigment spread was 6.38 mm, whereas in group II, it was 6.94 mm, showing a slightly higher pigment spread in group II, which was statistically not significant (P=0.301). There was no difference in response to therapy in patients having segmental vitiligo as compared with nonsegmental vitiligo. Cobblestoning, depigmentation of the grafts, infection, and graft displacement were the important side effects seen in some patients in both the groups. CONCLUSION: The study shows that the pigment spread with topical corticosteroid is comparable to that with PUVA. However, the studies with long-term follow-up are required to establish this. The advantages of topical corticosteroid are that its use is easy, less cumbersome, cheaper, and more cost effective than PUVA.

One-year trial on safety and normal linear growth with flunisolide HFA in children with asthma.

Flunisolide hydrofluoroalkane (HFA) has efficacy equivalent to that of flunisolide chlorofluorocarbon (CFC) at one third the dose of the CFC formulation, a reduction from 250 microg/puff for flunisolide CFC to 85 microg/puff for flunisolide HFA. Flunisolide HFA delivers a smaller particle size (1.2 microm) in solution, resulting in improved lung deposition as compared with flunisolide CFC (3.8 microm), which is delivered in suspension. An added built-in spacer has reduced oropharyngeal deposition that may result in fewer adverse events and make it easier to use. The objective of this study was to compare the year-long safety of flunisolide HFA (daily dosage 340 microg) with that of CFC beclomethasone dipropionate (BDP) (daily dosage 336 microg) and cromolyn sodium (daily dosage 6,400 microg) in children 4-11 years old with mild-to-moderate asthma. The effects of these drugs on linear growth and growth velocity were also compared. The study was a 1-year open-label, parallel-group trial. Changes in physical examinations (including growth), adverse events, vital signs, electrocardiograms, cosyntropin stimulation tests, mouth and throat cultures for Candida albicans, and laboratory findings were analyzed. Patients 4-5 years old received flunisolide HFA only. In total, 235 children were evaluated (152 receiving flunisolide HFA, 39 BDP, and 44 cromolyn). The incidence of adverse events was comparable among treatment groups; most were mild or moderate and considered unrelated to treatment. Among patients 6-11 years old, mean changes from baseline height at week 52 were 6.2 cm for the flunisolide HFA and cromolyn groups and 5.1 cm for the BDP group. Thus growth in children receiving flunisolide HFA was unaffected by 1 year of treatment. Changes from baseline in other parameters, including response to cosyntropin stimulation, were insignificant and similar among the 3 treatment groups. At the dosages studied, and following 1 year of treatment, flunisolide HFA with its small particle size and built-in spacer is safe and well tolerated in children 4-11 years old. There are no adverse effects associated with hypothalamic pituitary axis (HPA) function of flunisolide HFA, including linear growth in children 6-11 years old when compared with BDP and cromolyn sodium.

Flunisolide HFA.

Flunisolide is a synthetic corticosteroid approved for the treatment of persistent asthma and delivered by means of a metered-dose inhaler (MDI). A new formulation of flunisolide, using hydrofluoroalkane (HFA) as a propellant, has been developed to comply with the mandated worldwide phase-out of ozone-depleting chlorofluorocarbon (CFC) propellants. Aerosol particle size in the new flunisolide HFA solution is smaller than the flunisolide CFC suspension (1.2 vs 3.8 microm mass median aerodynamic diameter). Aerosol particle size is a key element in determining lung deposition and the regional distribution of inhaled medication within the lung. In addition, the flunisolide HFA MDI has been redesigned to include a built-in spacer. These features have improved distal lung deposition. Flunisolide HFA, at one-third the dosage (170 and 340 microg twice daily), had similar efficacy to flunisolide CFC (500 and 1000 microg twice daily) and significantly greater efficacy than placebo in a randomized, double-blind, placebo-controlled, 12-week study in patients with mild to moderate asthma. Flunisolide HFA was well tolerated in all trials. A long-term study found no suppression of adrenal function and minimal systemic effects were observed both in adults and children.

Topical flunisolide treatment of perennial rhinitis: clinical and immunological effects.

We studied the clinical and immunological effects of three months' treatment with intranasal flunisolide (100 micrograms daily) in 18 allergic patients with perennial rhinitis. 17 were hypersensitive to house dust mite and one to Parietaria pollen only. We found no significant changes in white blood cell count, serum levels of IgE and nasal IgA. However the treatment induced a marked improvement of clinical symptoms in all cases, and we observed a significant reduction of total IgE in nasal secretion. Flunisolide seems to exert this effect through its antiinflammatory action on the nasal mucosa.

Topical flunisolide treatment of perennial rhinitis: clinical and immunological effects.

We studied the clinical and immunological effects of three months' treatment with intranasal flunisolide (100 micrograms daily) in 18 allergic patients with perennial rhinitis. 17 were hypersensitive to house dust mite and one to Parietaria pollen only. We found no significant changes in white blood cell count, serum levels of IgE and nasal IgA. However the treatment induced a marked improvement of clinical symptoms in all cases, and we observed a significant reduction of total IgE in nasal secretion. Flunisolide seems to exert this effect through its antiinflammatory action on the nasal mucosa.

Contact dermatitis due to topical treatment with garlic in Hong Kong.

Contact dermatitis due to garlic is usually due to handling of garlic for cooking. Among the Chinese, garlic is also used as a form of topical medicament. 8 patients developed contact dermatitis after rubbing the cut end of a fresh garlic bulb onto the skin to treat fungal and other infections at the groin, neck, lower limb, hand or face. The distribution and morphology of the lesions were different from the classical form as described in the literature. Repeated open application tests with fresh garlic were all positive and patch tests with garlic extract were all negative. 5 controls tested by repeated open application with fresh garlic juice were also positive and patch tests in 10 controls with garlic extract were also negative. The results confirmed that the contact dermatitis was due to irritation. The patients were treated successfully with topical fluorinated steroid. For prevention, the practice of direct application of fresh garlic onto the skin for treating infections should be discouraged.

Irritant contact dermatitis due to a Chinese herbal medicine lu-shen-wan.

A Chinese herbal medicine Lu-Shen-Wan, which contains 6 ingredients, is sometimes applied topically to treat boils, carbuncles and other skin infections. 2 elderly women developed a rash after applying Lu-Shen-Wan. Patch tests showed positive reactions to Lu-Shen-Wan and to one of its 6 ingredients, Venenum Bufonis. A study in 15 control patients showed that 13 had positive reactions to 50% Lu-Shen-Wan and 50% Venenum Bufonis but that only 2 showed mild reactions when the concentration of the latter was reduced to 5%. The results suggest that Venenum Bufonis in Lu-Shen-Wan can cause irritant contact dermatitis. The present paper demonstrates that a Western dermatological investigative method, the patch test, is applicable to traditional medicine in confirming the cause of contact dermatitis from a Chinese herbal preparation and in identifying the causative ingredient. Such knowledge is very useful for the improvement of the preparation by reducing the concentration of the irritant, by removing it or by substituting it with an alternative non-irritant substance.

Treatment of seasonal allergic rhinitis with flunisolide and terfenadine.

A study of ninety-nine hay fever sufferers was conducted to compare the effect of treatment with flunisolide nasal spray plus terfenadine tablets with that of terfenadine alone. The study was carried out over an 11-week period, which covered the pollen season between May and August. All patients received 60 mg terfenadine twice daily and one group, of forty-nine patients, also received 50 mcg flunisolide to each nostril twice daily. Clinical assessments of nasal and ocular symptoms were made at admission and following 3, 7 and 11 weeks' treatment. An over-all evaluation of treatment effect was performed at each follow-up visit and nasal examination was carried out. Patients also completed diary cards daily. Both treatments were effective in reducing symptom severity, in comparison with previous seasons, but the combination treatment gave consistently better symptom relief. Statistically significant differences were detected in favour of the combined treatments group for nasal symptoms. Eye symptoms were found to be relieved to a comparable degree by both treatments. Results from daily patient self-assessments were consistent with these findings. The over-all evaluations by both patients and doctors were significantly in favour of flunisolide plus terfenadine. In conclusion, treatment of hay fever with flunisolide in addition to terfenadine was significantly more effective than treatment with the antihistamine alone.

[Modern therapy of mycosis fungoides]. / Moderne Therapie der Mycosis fungoides.

Mycosis fungoides (MF) treatment must be chosen only after staging extent of lymphoma. Stage I and II diseases respond best to either topical nitrogen mustard, photochemotherapy (PUVA), or electron beam. Chemotherapy of stage III and IV MF has only limited remission rates. Combinations of therapies and experimental approaches, such as monoclonal antibodies, may give longer survivals.