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Hydromoor

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Better_hydromoor

Company: Moorfields Pharmaceuticals.

Legal category: GMS reimbursable. Sport pending.

Active ingredient: Hypromellose 0.3% w/v.

Description: Preservative-free, sterile eye drops.

Presentation: 0.4ml-30 single dose units, €4.00.

Indications: Relief of dry eye symptoms associated with lack of natural tears or lubrication with rigid or gas permeable contact lenses.

Dosage: Adult-Child: One drop into each affected eye and close lid for 30 seconds. Elderly: As per adults.

Contraindications: Hypersensitivity to the active ingredient or to any of the excipients.

Special precautions: Discontinue and seek medical advice if irritation persists or worsens, or headache, eye pain, vision changes or continued redness occur. Driving/using machines (ensure vision has returned to normal). Pregnancy, lactation; seek medical advice.

Drug interactions: Wait 5 minutes before administering other eye drops.

Adverse drug reactions: None common.

Full prescribing information and references available from Moorfields Pharmaceuticals. Telephone: +44 207 684 9090. E-mail: pharmaceuticals@moorfieldspharmaceuticals.co.uk

For more details click here.

Tara Sweeney


Dovobet Gel Applicator

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W-Dovobet

Company: Leo Pharma.

Legal category: Prescription. GMS reimbursable. Sport permitted.

Active ingredient: Calcipotriol (hydrate)/betamethasone (dipropionate) 50mcg/0.5mg per g.

Description: Gel with applicator.

Presentation: 1 applicator-60g, €37.97.

Indications: Topical treatment of mild to moderate non-scalp plaque psoriasis vulgaris and scalp psoriasis.

Pharmacology: Calcipotriol is a vitamin D analogue. It induces differentiation and suppresses proliferation of keratinocytes. Betamethasone dipropionate has anti-inflammatory, antipruritic, vasoconstrictive and immunosuppresive properties.

Dosage: Adult: Apply once daily for 4 weeks (scalp), 8 weeks (non-scalp areas); if necessary, can be continued thereafter under medical supervision. Max. 15g daily. Do not exceed application to >30% body surface area. 1-4g/day is sufficient if used on scalp. Elderly: As per adults. Children: <18 years, not recommended.

Contraindications: Hypersensitivity to the active ingredient or to any of the excipients. Calcium metabolism disorders. Erythrodermic, exfoliative and pustular psoriasis. Viral skin lesions, fungal/ bacterial skin infections, parasitic infections, skin manifestations in relation to tuberculosis, perioral dermatitis, atrophic skin, striae atrophicae, skin vein fragility, ichthyosis, acne vulgaris, acne rosacea, rosacea, ulcers, wounds.

Special precautions: Avoid face, mouth, eyes, genitals. Wash hands after application. Avoid use on large areas of damaged skin, under occlusive dressings, mucous membranes, skin folds. Avoid excessive exposure to natural/ artificial sunlight. Risk of hypercalcaemia at doses >15g daily. Treat secondary infections (discontinue if worsen). Risk of generalised pustular psoriasis/rebound effects on discontinuation; continue medical supervision post-treatment. Long-term use, discontinue if adverse reactions occur. Guttate psoriasis; severe renal/hepatic impairment (no data). Pregnancy (assess risk/benefit), lactation (do not use on breast). Contains butylhydroxytoluene (E321).

Drug interactions: Avoid: Other steroids.

Adverse drug reactions: Pruritus.

Full prescribing information and references available from Leo Pharma. Telephone: (01) 490 8924.

Tara Sweeney

Catephen

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Catephen Box (Opt09)

Company: Kora Healthcare.

Legal category: Prescription. GMS reimbursable. Sport permitted.

Active ingredient: Camellia sinensis (green tea) leaf extract 100mg/g.

Description: Ointment.

Presentation: 15g tube, €42.59.

Indications: Cutaneous treatment of external genital and perianal warts (condylomata acuminata) in immunocompetent patients.

Pharmacology: Green tea leaf extract acts by inhibiting the growth of activated keratinocytes and by anti-oxidative effects at the site of application.

Dosage: Adult: Up to 250mg as total single dose (approx. 0.5cm of ointment strand) three times daily (maximum) until clearance of warts. Maximum duration 16 weeks in total (even if new warts develop). Elderly: As per adults. Children: Under 18 years, not recommended.

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Pregnancy.

Special precautions: Not recommended: Unhealed skin from surgical/ drug treatment, multiple treatment courses. Do not use in patients with severe hepatic impairment. Avoid contact with mucous membranes, open wounds, broken or inflamed skin. Do not expose treated area to sunlight or UV irradiation. Vulvar region genital warts (caution, associated with severe local adverse reactions). Uncircumcised males with warts under foreskin, stop treatment if signs of stricture occur. Temporary mild local skin reactions may occur; suspend treatment if severe or associated with lymph node reaction. Exclude genital herpes if vesicular local reaction occurs. May weaken condoms and vaginal diaphragms (wash off before sexual contact), consider additional methods of contraception. Lactation. Contains propylene glycol monopalmitostearate, isopropyl myristate.

Drug interactions: Immunomodulatory drugs. Avoid: Other local treatments, high-dosed oral green tea extract preparations.

Adverse drug reactions: Local application site reactions: Erythema, pruritus, irritation/burning, pain, ulcer, oedema, induration, vesicles, exfoliation, discharge, bleeding, swelling. Inguinal lymphadenitis/lymphadenopathy, phimosis.

Full prescribing information and references available from Kora Healthcare. Telephone: 01-8900406.

E-mail: medinfo@korahealthcare.com

Tara Sweeney

Aripiprazole Sandoz

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W-Aripiprazole

Company: Rowex Ltd.

Legal category: Prescription. GMS reimbursable. Sport permitted.

Active ingredient: Aripiprazole 5mg, 10mg, 15mg, 30mg.

Description: Blue, pink, yellow, pink, mottled, round tablet marked SZ on one side and 444, 446, 447 or 449 on reverse, respectively.

Presentation: 5mg-28, €45.75; 10mg-28, €43.76; 15mg-28, €43.76; 30mg-28, €78.65.

Indications: Treatment of schizophrenia in adults and adolescents. Treatment of moderate to severe manic episodes in Bipolar I Disorder in adults and (up to 12 weeks) in adolescents. Prevention of a new manic episode in aripiprazole-responsive adults.

Pharmacology: Aripiprazole’s efficacy is proposed to be mediated through a combination of partial agonism at dopamine D2 and serotonin 5HT1a receptors and antagonism of serotonin 5HT2a receptors.

Dosage: Adult: Schizophrenia: Initially 10 or 15mg/day. Maintenance, 15mg once daily. Maximum 30mg daily. Manic episodes: Initially 15mg once daily as monotherapy or combination therapy. Maximum 30mg daily. Recurrent manic episodes prevention: Continue monotherapy or combination therapy at same dose. Consider dose adjustments as indicated. Adjust dose if taken with potent CYP3A4 or CYP2D6 inhibitors or potent CYP3A4 inducers. See SPC. Severe hepatic impairment: Maximum 30mg daily (caution). Elderly: Consider lower starting dose. Children: Schizophrenia: 15 years and older, 10mg once daily (initially 2mg using appropriate aripiprazole-containing drug for 2 days, titrated to 5mg for 2 additional days to reach 10mg daily). When appropriate, increase in 5mg increments (maximum 30mg daily). Under 15 years, not recommended. Manic episodes in Bipolar I Disorder:  13 years and older, 10mg once daily (initially 2mg using appropriate aripiprazole-containing drug for 2 days, titrated to 5mg for 2 additional days to reach 10mg daily). Treat for minimum duration necessary (maximum 12 weeks). Only use >10mg/day in exceptional cases with close clinical monitoring. Under 13 years, not recommended.

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Pregnancy (assess risk/benefit), lactation.

Special precautions: Do not use for dementia-related psychosis. Caution: Cardiovascular disease, cerebrovascular disease, predisposition for hypotension or hypertension, family history of QT prolongation, history of seizure disorder, seizure-associated conditions, risk for aspiration pneumonia. Venous thromboembolism reported with antipsychotic agents; identify risk factors before and during treatment. Consider dose reduction and close monitoring if extrapyramidal symptoms occur. Monitor weight gain in adolescents with bipolar mania; consider dose reduction if gain is significant. Diabetics (or patients with risk factors). Supervise closely for suicidal behaviour, particularly those at high risk (especially early treatment and switching of therapy). History of pathological gambling (monitor carefully). Consider dose reduction or discontinuation if signs and symptoms of tardive dyskinesia occur. Discontinue if neuroleptic malignant syndrome or unexplained high fever develops. Hypersensitivity reactions may occur. Driving/using machines. Contains lactose.

Drug interactions: Stimulants (extreme caution in ADHD comorbidity). Caution: Drugs causing QT prolongation or electrolyte imbalance, alcohol or other CNS drugs. Certain antihypertensives, other serotonergics, drugs increasing aripiprazole concentrations.

Adverse drug reactions: Restlessness, insomnia, anxiety, extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache, blurred vision, gastrointestinal disorders, fatigue.

Full prescribing information and references available from Rowex Ltd. Telephone: 1800 304400. Fax: (027) 50417.
E-mail: rowex@rowa-pharma.ie

Tara Sweeney

Fingolimod (Gilenya) – Progressive Multifocal Leukoencephalopathy (PML) in a multiple sclerosis patient without previous treatment with natalizumab or other immunosuppressive medicines

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In April 2015 following agreement with the European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) and the HPRA, the marketing authorisation holder for fingolimod (Gilenya) highlighted information regarding the first case of progressive multifocal leukoencephalopathy (PML) in a patient treated with fingolimod who had not previously received natalizumab or other immunosuppressive medicines.

Fingolimod is authorised for use across the EU for treatment of adult patients as single disease modifying therapy in highly active relapsing remitting multiple sclerosis.

This first case of PML was reported in a patient receiving fingolimod for over four years. PML was suspected on a routine brain MRI scan and confirmed by positive JC virus DNA in cerebrospinal fluid (CSF) using quantitative PCR. Fingolimod was stopped immediately and the patient has not been reported to have experienced any clinical signs or symptoms related to PML. Health care professionals are reminded to be vigilant in relation to the risk of PML in patients treated with fingolimod. Based on this information, healthcare professionals should be aware of the advice outlined below.

 

Advice for Healthcare Professionals

  • A first report of PML in a multiple sclerosis patient taking fingolimod who had not previously received natalizumab or other immunosuppressive medicines has been received.
  • PML can present with similar features to multiple sclerosis as both are demyelinating diseases.
  • Patients should be appropriately informed about the risk of PML.
  • Healthcare professionals are recommended to be vigilant for the risk of PML in patients treated with fingolimod and to permanently discontinue treatment if PML is confirmed.

 

Key message

  • A first case of PML has been reported in a patient receiving fingolimod for over 4 years.
  • Healthcare professionals are reminded to be vigilant in relation to the risk of PML with fingolimod and to permanently discontinue treatment if PML is confirmed.
  • All suspected adverse reactions associated with fingolimod should be reported to the HPRA (www.hpra.ie).

 

*Further details on Gilenya are available at www.hpra.ie and www.ema.europa.eu/ema/

Caroline McDermott

Proton Pump Inhibitors (PPIs) – very rare reports of subacute cutaneous lupus erythematosus (SCLE)

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Proton pump inhibitors (PPIs)* are indicated in the treatment of gastric and duodenal ulcers, NSAID-associated ulcers, gastro-oesophageal reflux, Zollinger-Ellison syndrome and in combination with antibacterial therapy for eradication of Helicobacter pylori. Some products are indicated for short-term use to treat reflux symptoms in adults (see individual SmPCs on www.hpra.ie for full details of licensed indications).

Reports of subacute cutaneous lupus erythematosus (SCLE) in association with PPIs have been reviewed by the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC). The signal of an association was originally triggered by a retrospective medical chart review of patients diagnosed with SCLE over a 19-year period1. Overall the cases were well documented with supporting biopsy and serological tests. These cases were supported by a case control study2 which showed an increased risk of SCLE in patients exposed to PPIs.

Taking into consideration the relevant data across all substances in the class, including some cases with positive re-challenge, the evidence from published literature, and the likelihood of under-reporting given that photosensitivity is a known side-effect of PPIs, the PRAC agreed that the product information of medicinal products containing PPIs should be amended to reflect the risk of SCLE.

 

Advice for Healthcare Professionals

  • PPIs are associated with very infrequent cases of SCLE. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should be advised to seek medical help promptly and the health care professional should consider stopping the PPI.
  • SCLE after previous treatment with a PPI may increase the risk of SCLE with other PPIs.
  • The product information (Summary of Product Characteristics (SmPC) and Package Leaflet (PL)) for all PPIs (prescription and non-prescription) will be updated to reflect this information.

 

Key message

  • PPIs are associated with very infrequent cases of SCLE.

 

*The active substances included in this review were omeprazole, esomeprazole, rabeprazole, pantoprazole, lansoprazole and dexlansoprazole. See www.hpra.ie for authorised product names and SmPCs for indications.

 

References

1. Sandholt LH, Laurinavicience R, Bygum A. Proton pump inhibitor-induced subacute cutaneous lupus erythematosus. Br J Dermatol. 2014;170:342-51

2. Gronhagen CM, Forced CM, et al. Subacute cutabeous lupus erythematosus and its association with drugs: a population based matched case-control study of 234 patients in Sweden. Br J Dermatology. 2012; 167:296-305

Caroline McDermott

Overview of Disease-Modifying Treatments in Multiple Sclerosis

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Download PDF

Diagnosis of Multiple Sclerosis

Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating, degenerative disease of the central nervous system (CNS). During the early phases of the disease, the integrity of the blood-brain barrier (BBB) is compromised, permitting the invasion of monocytes and T cells into the brain parenchyma, resulting in the demyelination characteristic of MS lesions.1,2

The revised McDonald Criteria for the diagnosis of MS, which include both clinical criteria and specific magnetic resonance imaging (MRI) findings, has resulted in the earlier diagnosis of MS with a high degree of both specificity and sensitivity. This allows for better counselling of patients and earlier treatment.3

The typical clinical course of MS is relapsing-remitting, characterised by an initial event of acute or subacute neurological disturbance, generally indicated as clinically isolated syndrome (CIS) followed by recurrence of symptoms over time. CIS is the type of onset in around 85% of MS cases, while the remaining 15% of patients have a progressive disease from onset (primary progressive (PP) MS). CIS is distinguished from radiologically isolated syndrome (RIS), in which patients have incidentally detected MRI T2 bright foci suggestive of demyelination in the absence of clinical symptoms.2,4

One of the primary motivations for early diagnosis of MS is the potential for early treatment to delay the onset of additional clinical relapses and to possibly delay long-term disability. The first opportunity to initiate disease-modifying treatment (DMT) in patients with MS is often when they are in the CIS stage. Clinical trials have demonstrated the benefit of DMTs in delaying or preventing patients with high-risk CIS from converting to clinically definite MS. For patients with a CIS when the diagnosis of MS cannot yet be established according to the revised McDonald criteria, only beta interferons and glatiramer acetate are approved by the regulatory agencies.2,5

The results of numerous studies assessing the risk of conversion from CIS to clinically definite MS, suggest that patients who have asymptomatic brain MRI lesions at the time of presentation of CIS have a 60 to 80% chance of developing clinically definite MS by 10 years, whereas those without brain lesions have approximately a 20% risk of clinically definite MS by 10 years.2

 

Classification of Multiple Sclerosis6

Relapsing-Remitting MS (RRMS)

  • 85% of patients who develop MS have RRMS
  • Severity varies greatly in from individual to individual.
  • Initial average annual relapse rate of about 2-2.5, dropping to approximately one per year.
  • Frequent relapses, especially at disease onset, considered as poor prognostic sign.
  • At 10 years after disease onset 50% of patients will enter the SPMS phase, at 20 years this will rise to 80%.

Progressive-Relapsing MS (PRMS)

  • Can be identified as worsening Relapsing-Remitting MS (progressive disease with obvious relapses).
  • Important to identify in terms of treatment. Whether the patient with PRMS is already on disease modifying therapies or not, switching to other treatments such as Tysabri or Mitoxantrone may be crucial in prevention of further disease activity and slowing down the evolution from PRMS to SPMS.

Secondary-Progressive MS (SPMS)

  • Defined as progression of clinical disability (with or without relapses and minor fluctuations) after a relapsing-remitting onset.
  • Disability progresses even in between relapses.
  • Establishing when patients are converting from RRMS to SPMS can be difficult and only become apparent over a significant length of time.

Primary-Progressive MS (PPMS)

  • Approximately 10%-15% of the MS population and, as opposed to other forms of MS, with no female propensity.
  • Progressive from onset without discernible relapses or remissions.
  • Usually later age of onset (40’s onwards), though in rare cases can occur at an earlier age.
  • Typically presents with an increasing spastic gait already affecting quality of walking.
  • Poorer prognosis; it takes approximately 6 years to reach the Expanded Disability Status Scale (EDSS) of 6.

Benign MS

  • Isolated attacks with complete recovery, with little or no accumulation of disability.
  • The attacks may be separated by 10 years or more.
  • Often goes undiagnosed for several years and in many instances, is diagnosed post-mortem.

 

Currently Available Treatments7,8

DMTs can reduce the rate and frequency of relapses, and slow progression to disability. However, their long-term effect on clinical outcome is not yet fully known. There are a number of different DMTs currently available in Ireland, which allows for individualised treatment. Treatment decisions must balance the benefits of individual drugs with their risks and side-effects (see table 1 and 2).

 Beta interferons (IFN-β)

IFN-β is a type I interferon with anti-viral and anti- inflammatory characteristics. Potential mechanisms of action include decreased IFN-γ production and inhibition of antigen presentation leading to reduced activation of T cells, and reduction of T cell adhesion and proteases important for T cell entry across the BBB.

 Glatiramer acetate

GA is a random combination of four amino acids which has a structural similarity to myelin basic protein. It is thought to modulate immunity by shifting the T helper (Th)1 lymphocytes in MS patients towards a predominance of Th2 phenotype, which may contribute to disease amelioration.

 Natalizumab

Natalizumab is a monoclonal antibody to the αα4 subunit of αα4ββ1 integrin, a protein found on the surface of lymphocytes. αα4ββ1 integrins interact with the vascular-cell adhesion molecule 1 enabling adhesion of lymphocytes to the vascular endothelium. It prevents the transmigration of inflammatory lymphocytes across the BBB into the CNS.

 Alemtuzumab

Alemtuzumab is a humanised IgG1 monoclonal antibody directed against CD52, a small glycoprotein expressed on the surface of many types of white blood cells including T and B lymphocytes. Alemtuzumab lyses cells expressing CD52 by antibody-dependent cellular cytolysis. The reduction in the level of circulating B and T cells and subsequent repopulation, may reduce the potential for relapse, which ultimately delays disease progression.

 Fingolimod

Fingolimod is a sphingosine 1-phosphate (S1P) receptor modulator. S1P binds to S1P receptors predominantly on lymphocytes, signalling for them to exit lymph nodes and enter the circulation. Fingolimod binds to S1P receptors on naïve and activated lymphocytes, thus retaining them in lymph nodes, away from the CNS where they incite inflammation and tissue damage.

 Teriflunomide

Teriflunomide is an immunomodulatory agent with anti-inflammatory properties that selectively and reversibly inhibits dihydroorotate dehydrogenase (DHODH), a mitochondrial membrane protein essential for de novo pyrimidine synthesis. Inhibiting DHODH blocks high levels of lymphocyte proliferation. Teriflunomide does not kill resting lymphocytes – thus, previously acquired cellular immunity is not lost with treatment.

 Dimethyl fumarate

The exact mechanism of action by which DMF exerts its effect in MS is still unclear, but is thought to involve enhancement of endogenous mechanisms to counteract oxidative stress, via activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcriptional pathway.

 

Established vs Novel Treatments in MS7,8

The beta interferons and glatiramer acetate are established, effective treatments for which there is long-term clinical experience. Major advantages of the injectable DMTs include a known and favourable safety profile, long-term efficacy and established patient support services. They are also generally well tolerated despite the route of administration.

More recently, monoclonal antibodies have been developed which act through specific mechanisms, e.g. blocking α-4 integrin interactions (natalizumab), or lysing cells expressing CD52 (alemtuzumab). These agents can be highly effective, but sometimes have serious potential complications. Natalizumab is associated with an increased risk of progressive multifocal leukoencephalopathy (although anti-JCV antibody testing provides supportive information for risk stratification of treatment in individual patients), while alemtuzumab is associated with the development of new autoimmune disorders. Both of these agents are administered via intravenous infusion.

Three new oral therapies (fingolimod, teriflunomide and dimethyl fumarate) provide efficacy, tolerability and convenience. However, there are currently no long-term post-marketing efficacy and safety data in a general MS population.

Current data support the gradual introduction of orals as an option for patients with RRMS if there is any indication of a suboptimal response or intolerance or lack of adherence to the injectable treatments. Appropriate programs for monitoring adverse events are warranted.

 

Treatment Selection and Adherence

Determinants in DMT selection include disease type and activity (see table 2 for indications of individual agents), the benefit to risk assessment, and contraindications in the individual patient. However, patient preferences play an increasingly major role in treatment decision making.

A major issue with therapies in MS is that it is not clear to date whether they benefit subjects in the longer term and whether they fulfil the patients’ perception of benefit. In CIS they will need to be used for much longer in essentially asymptomatic subjects, and thus one might expect higher rates of dropout. Some of these issues will arise as a result of long-term administration of any therapy.

The prerequisites for a well-informed treatment decision by the patient are knowledge of the disease, treatment options and efficacy, potential side-effects and risks. Obtaining information regarding the patient’s knowledge of the disease is therefore important for counselling. A shared decision-making process is increasingly advocated as an ideal model of treatment decisions. It is important that patients are encouraged to establish their preference and are involved in the decision of choosing which treatment most suitable to them.

Good adherence to therapy is important in achieving the full beneficial effects of long-term treatments. It has been reported that 13 to 72% of patients do not adhere to disease-modifying MS treatments, and poor adherence or treatment gaps are associated with a higher rate of relapse.5

A simple starting point to promote adherence is educating patients about the necessity for therapy, while setting realistic expectations. Properly counselling patients before therapy is initiated can prevent problems with adherence further along the treatment course, e.g. although DMTs do not cure MS, through relapse reduction and delay in progression, they can help patients maintain function and quality of life. Patients who are in remission must understand that although they may not be experiencing relapses or signs of progression, the disease may be active at a subclinical level and thus, continuation of therapy is necessary to help reduce disease burden.9

Poor adherence is often caused by side-effects resulting in a negative impact on quality of life. It is therefore important that patients have realistic expectations of potential side-effects and that strategies to monitor and manage them are discussed in detail.

With injectable DMTs, only one-third of the reasons found to be responsible for poor adherence are dependent on the application form. This means that non-injection related factors of nonadherence play a major role, as is known from chronic disorders like epilepsy or hypertension.5

Other barriers to maintaining treatment adherence in patients with MS include forgetting the medication, and issues with complacency and treatment fatigue.9

The use of electronic devices with recording dose history provides useful data on forgetfulness and helps identify non-adherent patients using injectable DMTs.

In the currently growing field of MS therapeutics, patient counselling and perceiving patients’ attitudes will be of huge importance for treatment selection and adherence aiming at clinical stability and optimal quality of life. Proper management of treatment expectations should be used to promote adherence, reinforce perceived effectiveness, and minimise adverse events.9,10

 

Table 1. Disease-Modifying Treatments in Multiple Sclerosis – Efficacy and Main Side-Effects7,8

Table 1 DMTs in MS - Efficacy and Main Side-Effects

Click on image to enlarge

 

Table 2. Disease-Modifying Treatments in Multiple Sclerosis – List of Agents Available in Ireland

Table 2 DMTs in MS - List of Agents Available in Ireland

Click on image to enlarge

 

Abbreviations:

MS: multiple sclerosis; CNS: central nervous system; MRI: magnetic resonance image; CIS: clinically isolated syndrome; RIS: radiologically isolated syndrome; DMT: disease-modifying treatment; RRMS: Relapsing-Remitting MS; PRMS: Progressive-Relapsing MS; SPMS: Secondary-Progressive MS; PPMS: Primary-Progressive MS; EDSS: Expanded Disability Status Scale; S1P: sphingosine 1-phosphate; DHODH: dihydroorotate dehydrogenase; Nrf2: nuclear factor (erythroid-derived 2)-like 2; PML: progressive multifocal leukoencephalopathy; ARR: annualised relapse rate; WBCs: white blood cells; RTIs: respiratory tract infections; BP: blood pressure; GI: gastrointestinal; CBCs: complete blood counts; SC: subcutaneous; IM: intramuscular; IV: intravenous; BBB: blood-brain barrier; CDMS: clinically definite MS; admin: administration.

 

References:

1. Larochelle C et al. FEBS Lett 2011;585:3770–3780. 2. Marcus JF and Waubant EL. Neurohospitalist 2012;3(2):65-80. 3. Polman CH et al. Ann Neurol. 2011 Feb; 69(2):292–302. 4. Gajofatto A et al. Dis Markers 2013;35( 6):687–699. 5. Bayas A and Mäurer M. Patient Prefer Adherence 2015;9:265–274. 6. HSE (September 2012). Handbook for nurses and midwives caring for people with Multiple Sclerosis. A guide to support practice. 7. Cross AH and Naismith RT. J Intern Med 2014;275(4):350-63. 8. Nicholas R et al. Drug Des Devel Ther 2011;5:255–274. 9. Costello K et al. Medscape J Med. 2008;10(9): 225. 10. Di Battista et al. Mult Scler Int 2014. Article ID 752318.

 

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Caroline McDermott

Taptiqom

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W-Taptiqom

Company: Santen.

Legal category: Prescription. GMS reimbursable. Sport prohibited in specific sports.

Active ingredients: Tafluprost/timolol (as maleate) 15mcg/5mg per ml.

Description: Preservative-free, sterile, eye drops.

Presentation: 0.3ml-30 single-dose units, €19.50.

Indications: Reduction of intraocular pressure (IOP) in open angle glaucoma or ocular hypertension in patients insufficiently responsive to topical monotherapy with beta-blockers or prostaglandin analogues who require combination therapy and would benefit from preservative-free eye drops.

Pharmacology: The combination of tafluprost and timolol lower IOP by complementary mechanisms of action and the combined effect results in additional IOP reduction compared to either compound alone. Tafluprost is a fluorinated analogue of prostaglandin F2α. It increases the uveoscleral outflow of aqueous humour. Timolol maleate is a non-selective beta-adrenergic receptor blocking agent. Its mechanism of action, which is not clearly established, may be related to reduced aqueous formation.

Dosage: Adult: One drop in the conjunctival sac of affected eye(s) once daily (maximum). Discard unused solution immediately after use. Elderly: As per adults. Children: Under 18 years, not recommended.

Contraindications: Hypersensitivity to the active substances or to any of the excipients. Reactive airway disease including bronchial asthma, history of bronchial asthma, severe chronic obstructive pulmonary disease (COPD). Sinus bradycardia, sick sinus syndrome including sino-atrial block, second or third degree atrioventricular block not controlled with pace-maker. Overt cardiac failure, cardiogenic shock. Pregnancy (unless clearly necessary), lactation.

Special precautions: Inform patients of possibility of eyelash growth, darkening of eyelid skin and increased iris pigmentation (may be permanent). Caution: First degree heart block, severe peripheral circulatory disturbance/disorders, mild/moderate COPD, spontaneous hypoglycaemia, labile diabetes, corneal diseases, renal/hepatic impairment, aphakic patients, pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, risk factors for cystoid macular oedema or iritis/uveitis. Systemic effects may occur. Cardiovascular diseases (assess risk/benefit). May mask hyperthyroidism (avoid abrupt withdrawal). History of atopy or severe anaphylactic reactions. Choroidal detachment reported after filtration procedures. Angle-closure glaucoma (add a miotic). Neovascular, angle-closure, narrow-angle or congenital glaucoma (no experience). Aphakic patients, pigmentary or pseudoexfoliative glaucoma (limited experience). Remove contact lenses prior to instillation, wait 15 minutes before reinserting. Driving/using machines (ensure clear vision).

Drug interactions: Administer other ophthalmic products at least 5 minutes apart. Use of 2 topical beta-blockers not recommended. Anaesthesia, oral calcium channel blockers, beta-adrenergic blocking agents, antiarrhythmics, digitalis, parasympathomimetics, guanethidine, CYP2D6 inhibitors, epinephrine.

Adverse drug reactions: Conjunctival/ocular hyperaemia, eye pruritus, eye pain, eye irritation, eyelash changes (increased length/ thickness/ number, discolouration), foreign body sensation in eyes, blurred vision, photophobia. Full prescribing information and references available from Santen. Telephone: +353 1 695 0008.

E-mail: medinfo@santen.co.uk.

Tara Sweeney


Synjardy ▼

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Company: Boehringer Ingelheim Ltd.

Legal category: Prescription. GMS reimbursable. Sport permitted.

Active ingredients: Empagliflozin/metformin hydrochloride 5/850mg, 5/1000mg, 12.5/850mg, 12.5/1000mg.

Description: Yellowish white, brownish yellow, pinkish white or dark brownish purple, oval, biconvex film coated tablets marked with S5 or S12 and logo on one side and strength on reverse.

Presentation: 56, €42.00.

Indications: Treatment of type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control when maximally tolerated doses of metformin (alone or with other glucose-lowering agents including insulin) not adequate or patient already treated with empagliflozin and metformin separately.

Pharmacology: Empagliflozin, an SGLT2 inhibitor, and metformin hydrochloride, a biguanide, have complementary mechanisms of action which improve glycaemic control. SGLT2 is responsible for the reabsorption of glucose from the glomerular filtrate back into the circulation. Empagliflozin reduces renal glucose reabsorption which leads to excess urinary glucose excretion which, in addition, triggers calorie loss, associated with body fat loss and body weight reduction and also mild diuresis which contributes to blood pressure reduction. Metformin lowers both basal and postprandial plasma glucose. It may act by reducing hepatic glucose production, by increasing insulin sensitivity or by delaying intestinal glucose absorption. It stimulates intracellular glycogen synthesis by acting on glycogen synthase. It increases the transport capacity of membrane glucose transporters and it reduces total cholesterol, LDL cholesterol and triglyceride levels.

Dosage: Adult: Swallow whole, twice daily with meals. Inadequate control on metformin: Initial dose should provide 5mg empagliflozin twice daily plus metformin dose similar to dose already being taken. Can increase to 12.5mg empagliflozin twice daily. Switching from empagliflozin and metformin: Initiate at same total daily empagliflozin dose already being taken and metformin dose similar to dose already being taken. As add-on therapy with sulphonylurea (SU) or insulin: Consider lower dose of SU or insulin. Elderly: 85 years and older, initiation not recommended. Children: Under 18 years, not recommended.

Contraindications: Hypersensitivity to the active ingredients or to any of the excipients. Diabetic ketoacidosis, diabetic pre-coma, renal failure or renal dysfunction,  acute conditions with potential to alter renal function, acute/ chronic disease which may cause tissue hypoxia, hepatic impairment, acute alcohol intoxication, alcoholism. Pregnancy, lactation.

Special precautions: Do not use in moderate or severe renal impairment, type 1 diabetes. Caution: Patients for whom an empagliflozin-induced drop in blood pressure could pose a risk (cardiovascular disease, elderly (≥75 years), on anti-hypertensives with history of hypotension). Conditions leading to fluid loss, carefully monitor volume status and electrolytes; consider temporary interruption. Monitor renal function prior to initiation and at least yearly thereafter; at least 2-4 times a year if serum creatinine levels at upper limit of normal and in elderly. Assess for lactic acidosis risk factors. Discontinue and hospitalise immediately if metabolic acidosis suspected. Suspend 48 hours before surgery; resume 48 hours after surgery if renal function normal. Suspend prior to iodinated contrast agents, resume 48 hours after if renal function normal. Consider suspending if complicated urinary tract infections (e.g. pyelonephritis or urosepsis) occur. Cardiac failure NYHA class I-II (limited experience), NYHA class III-IV (no experience). Driving/using machines (avoid hypoglycaemia).

Drug interactions: Avoid: Alcohol, UGT inducers. Not recommended: Renally eliminated cationic drugs. Caution: Initiating antihypertensives/ NSAIDs, diuretics, glucocorticoids, β2-agonists. Positive urine test for glucose.

Adverse drug reactions: Hypoglycaemia (when used with SU or insulin), gastrointestinal upset, vaginal moniliasis, vulvovaginitis, balanitis and other genital infection, urinary tract infection, taste disturbance, generalised pruritus, increased urination.

Full prescribing information and references available from Boehringer Ingelheim Ltd. Telephone: +44 (0) 1344 742579. E-mail: medinfo.bra@boehringer-ingelheim.com

Tara Sweeney

Spiolto Respimat

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Spiolto Respimat - Device Only (High Res)

Company: Boehringer Ingelheim Ltd.

Legal category: Prescription. Sport prohibited. GMS reimbursable.

Active ingredients: Tiotropium (bromide monohydrate)/ olodaterol (hydrochloride) 2.5/2.5mcg per puff.

Description: Inhalation solution.

Presentation: 30 dose unit, €42.00.

Indication: Maintenance bronchodilator treatment of chronic obstructive pulmonary disease (COPD).

Pharmacology: Tiotropium bromide and olodaterol (LAMA/ LABA combination) provide additive bronchodilation due to their different modes of action which provides optimal bronchodilatation in all regions of the lungs. Tiotropium is a long-acting muscarinic receptor antagonist which competitively and reversibly binds to M3 receptors in bronchial smooth musculature, antagonising the cholinergic (bronchoconstrictive) effects of acetylcholine, resulting in bronchial smooth muscle relaxation. Olodaterol is a long acting beta2-adrenergic agonist. Activation of beta2-adrenoceptors in the airways results in stimulation of intracellular adenyl cyclase, an enzyme that mediates synthesis of cyclic-3’,5’ adenosine monophosphate (cAMP). Elevated levels of cAMP induce bronchodilation by relaxation of airway smooth muscle cells.

Dosage: Adult: Two puffs once daily at same time of the day (maximum). Elderly: As per adults. Children: Under 18 years, no relevant use.

Contraindications: Hypersensitivity to the active substances or to any of the excipients. History of hypersensitivity to atropine or its derivatives (e.g. ipratropium, oxitropium).

Special precautions: Not for use in asthma or acute episodes of bronchospasm. Discontinue immediately if paradoxical bronchospasm occurs. Caution: Narrow-angle glaucoma, prostatic hyperplasia, bladder-neck obstruction, cardiovascular disorders, especially ischaemic heart disease, severe cardiac decompensation, cardiac arrhythmias, hypertrophic obstructive cardiomyopathy, hypertension, aneurysm, convulsive disorders, thyrotoxicosis, QT interval prolongation, patients unusually responsive to sympathomimetic amines, myocardial infarction during previous year, unstable or life-threatening cardiac arrhythmia, hospitalisation for heart failure during previous year, paroxysmal tachycardia (>100 beats per minute). May need to discontinue if clinically significant cardiovascular effects occur. May occur: Significant hypokalaemia, plasma glucose increases. May be associated with dental caries with long term use. Moderate renal impairment. Severe renal impairment (limited experience). Severe hepatic impairment (no data). Driving/using machines (caution). Pregnancy (avoid), lactation (assess risk/benefit).

Drug interactions: Avoid: Other drugs containing long-acting β2-adrenergic agonists. Not recommended: Other anticholinergic containing drugs. Caution: Halongenated hydrocarbon anaesthetics, cardioselective β-blockers. Other adrenergic agents, xanthine derivatives, steroids, non-potassium sparing diuretics, β-adrenergic blockers, monoamine oxidase inhibitors, tricyclic antidepressants, QTc prolonging drugs.

Adverse drug reactions: Dry mouth.

Full prescribing information and references available from Boehringer Ingelheim Ltd. Telephone: +353 1 2959620. E-mail: medinfo.bra@boehringer-ingelheim.com.

Tara Sweeney

Jext

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Company: ALK-Abello Ltd.

Legal category: Prescription. GMS reimbursable. Sport prohibited in competition.

Active ingredient: Adrenaline (tartrate) 150mcg/ 0.15ml, 300mcg/ 0.30ml.

Description: Solution for injection in pre-filled pen.

Presentation: 1, €32.79.

Indications: Emergency treatment of anaphylaxis caused by insect stings/bites, foods, drugs and other allergens as well as idiopathic or exercise induced anaphylaxis.

Pharmacology: Adrenaline is a catecholamine which stimulates the sympathetic nervous system (both alpha and beta receptors) by which cardiac rate, cardiac output and coronary circulation is raised. It alleviates wheezing and dyspnoea through its action on beta receptors on bronchial smooth muscles which causes bronchial smooth muscle relaxation.

Dosage: Adult: 300mcg by single intramuscular injection into anterolateral thigh. If required repeat dose after 5-15 minutes. Seek immediate medical attention following administration. Elderly: As per adults. Children: Over 30kg, as per adults. Between 15-30kg, 150mcg. Under 15kg, not recommended unless life-threatening situation and under medical advice.

Contraindications: None in allergic emergency.

Special precautions: Do not inject into buttock. Caution: Hyperthyroidism, cardiovascular diseases (including angina pectoris, obstructive cardiomyopathy, cardiac arrhythmia, cor pulmonale, atherosclerosis, hypertension), phaeochromocytoma, narrow angle glaucoma, severe renal impairment, prostatic adenoma leading to residual urine, hypercalcaemia, hypokalaemia, diabetes, elderly, asthma. Pregnancy (assess risk/benefit). Driving/using machines. Contains sodium metabisulfite (E223).

Drug interactions: Caution: Drugs that may sensitise the heart to arrhythmias including digitalis, quinidine. Tricyclic antidepressants, monoamine oxidase inhibitors, catechol-O-methyl transferase inhibitors, alpha- and beta-blockers, parasympathomimetics.

Adverse drug reactions: Frequency not established.

Full prescribing information and references available from ALK-Abello Ltd. Telephone: +44 118 903 7940.

E-mail: info@uk.alk-abello.com

Tara Sweeney

Altavita D3

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W-Altavita

Company: Consilient Health Ltd.

Legal category: Prescription. GMS reimbursable. Sport permitted.

Active ingredient: Colecalciferol (vitamin D3) 25000 IU/ml.

Description: Oral solution.

Presentation: 3 X 1 ampoules, €5.56.

Indications: Prevention and treatment of vitamin D deficiency. As an adjunct to specific therapy for osteoporosis.

Pharmacology: Vitamin D stimulates intestinal calcium absorption, incorporation of calcium into the osteoid, and release of calcium from bone tissue. In the small intestine it promotes rapid and delayed calcium uptake. The passive and active transport of phosphate is also stimulated. In the kidney, it inhibits the excretion of calcium and phosphate by promoting tubular resorption. It directly inhibits production of parathyroid hormone (PTH) in the parathyroids. PTH secretion is inhibited additionally by the increased calcium uptake in the small intestine under the influence of biologically active vitamin D.

Dosage: Adult: Preferably take with meal. Prevention or as adjunct to osteoporosis therapy: 25000 IU/month. Treatment: 50000 IU/week for 6-8 weeks, followed by maintenance therapy (may require 1400-2000 IU/day); measure 25(OH) D three to four months after initiating maintenance therapy. Children: Prevention: 0-1 years, 25000 IU every 8 weeks; 1-18 years, 25000 IU every 6 weeks. Treatment: 0-18 years, 25000 IU every 2 weeks for 6 weeks (followed by maintenance therapy of 400-1000 IU/day).

Contraindications: Hypersensitivity to the active ingredient or to any of the excipients. Hypercalcaemia/hypercalciuria, nephrolithiasis, nephrocalcinosis, severe renal impairment, hypervitaminosis D, pseudohypoparathyroidism. Pregnancy, lactation.

Special precautions: High risk patients may require higher doses and monitoring of serum 25(OH)D: Institutionalised or hospitalised patients, patients with dark skin or limited effective sun exposure, obesity, patients under evaluation for osteoporosis, malabsorption (including inflammatory bowel/coeliac disease), recent treatment for vitamin D3 deficiency requiring maintenance therapy. Caution: Renal impairment (monitor calcium and phosphate levels; consider risk of soft tissue calcification), sarcoidosis (monitor calcium in serum and urine). Risk for renal stones (consider calcium supplementation under close medical supervision).

Drug interactions: Caution: Digitalis and other cardiac glycosides. Anticonvulsants, barbiturates, thiazide diuretics, glucocorticoids, ion exchange resins, laxatives, actinomycin, imidazole antifungal agents.

Adverse drug reactions: None common.

Full prescribing information and references available from Consilient Health Ltd. Telephone: (01) 2057760.

Tara Sweeney

Risk of diabetic ketoacidosis during treatment with SGLT2 inhibitors

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SGLT2 inhibitors include canagliflozin, dapagliflozin and empagliflozin alone or in combination with metformin, which are authorised for the treatment of type 2 diabetes mellitus.

 

Serious and sometimes life-threatening cases of diabetic ketoacidosis in patients treated with SGLT2 inhibitors have been reported, the majority of which required hospitalisation. Up to half of these cases occurred during the first two months of treatment and one third of the cases concerned off-label use in patients with type 1 diabetes. In some cases, just before or at the same time as the ketoacidosis occurred, patients experienced dehydration, low food intake, weight loss, infection, surgery, vomiting, a decrease in their insulin dose or poor control of diabetes. In a number of cases atypical moderately increased glucose values or glucose values below 14 mmol/l (250 mg/dl) were reported, whereas hypoglycaemia was reported in one case. There were also cases of ketoacidosis shortly after discontinuation of SGLT2 inhibitors.

 

The underlying mechanism for SGLT2 inhibitor-associated diabetic ketoacidosis is not established. Diabetic ketoacidosis usually develops when insulin levels are too low. Diabetic ketoacidosis occurs most commonly in patients with type 1 diabetes and is usually accompanied by high blood glucose levels (>14 mmol/l). However, in a number of cases described above, blood glucose levels were only slightly increased, in contrast to typical cases of diabetic ketoacidosis.

 

Prescribers should inform patients of the signs and symptoms of metabolic acidosis (such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue and sleepiness) and advise them to immediately seek medical advice if they develop such signs and symptoms. It is recommended that patients taking SGLT2 inhibitors should be assessed for ketoacidosis when they present with signs or symptoms of metabolic acidosis in order to prevent delayed diagnosis and management. If ketoacidosis is suspected, treatment with SGLT2 inhibitors should be discontinued. If ketoacidosis is confirmed, appropriate measures should be taken to correct the ketoacidosis and to monitor glucose levels.

 

This information was recently highlighted in a Direct Healthcare Professional Communication (DHPC) from the marketing authorisation holders. The Health Products Regulatory Authority (HPRA) is currently participating in an EU evaluation of the risk of diabetic ketoacidosis with SGLT2 inhibitors and any new advice following completion of this review will be communicated promptly. In the meantime, healthcare professionals are requested to report any suspected adverse reactions associated with use of these products to the HPRA, preferably via the online report form accessible from the website at www.hpra.ie.

 

Advice for Healthcare Professionals

  • Serious, sometimes life-threatening cases of diabetic ketoacidosis have been reported in patients on SGLT2 inhibitor treatment for type 2 diabetes.
  • In a number of these reports, the presentation of the condition was atypical with only moderately increased blood glucose levels observed. Such atypical presentation of diabetic ketoacidosis in patients with diabetes could delay diagnosis and treatment.
  • Prescribers should inform patients of the signs and symptoms of metabolic acidosis and advise them to immediately seek medical advice if they develop relevant signs and symptoms
  • Patients on SGLT2 inhibitors should be tested for ketones when they present with symptoms of acidosis in order to prevent delayed diagnosis and patient management.
  • Cases of diabetic ketoacidosis were also reported in patients with type 1 diabetes who were given SGLT2 inhibitors. Prescribers are reminded that type 1 diabetes is not an approved indication for this drug class.

 

Key message

  • Serious, sometimes life-threatening cases of diabetic ketoacidosis have been reported in patients treated with SGLT2 inhibitors, some of which have presented atypically, with only moderately increased blood glucose levels observed
  • If ketoacidosis is suspected, treatment with SGLT2 inhibitors should be discontinued. If ketoacidosis is confirmed, appropriate measures should be taken to correct the ketoacidosis and to monitor glucose levels.
  • Any suspected adverse reactions associated with SGLT2 inhibitors should be reported to the HPRA

 

*Brands include Invokana, Vokanamet, Forxiga, Xigduo, Jardiance and Synjardy

Caroline McDermott

Donepezil – Reports of Rhabdomyolysis

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Donepezil* is a specific and reversible inhibitor of acetylcholinesterase which has been authorised in Ireland since 1997 for use for the symptomatic treatment of mild to moderately severe Alzheimer’s dementia.

 

Reports of rhabdomyolysis associated with donepezil were recently reviewed by the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC). Rhabdomyolysis is a clinical and biochemical syndrome that results from the breakdown of skeletal muscle and the release of intracellular contents into the circulatory system. Rhabdomyolysis can cause serious and sometimes fatal abnormal heart rhythms, kidney damage and kidney failure, but is generally treatable if recognised promptly.

 

The PRAC considered cases of rhabdomyolysis from post-marketing spontaneous reports and clinical trials. Whilst the individual cases do not provide strong evidence of a causal association between donepezil and rhabdomyolysis, based on the cumulative information from 11 cases in particular, a causal or contributory role for donepezil in these cases of rhabdomyolysis and other less serious muscle disorders including weakness and pain cannot be excluded.

 

Rhabdomyolysis has been reported to occur independently of Neuroleptic Malignant syndrome (NMS) and in close temporal association with donepezil initiation or dose increase.

 

Rhabdomyolysis can also be a feature of NMS, a potentially life-threatening condition characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatine phosphokinase levels. NMS has been reported to occur very rarely in association with donepezil, particularly in patients also receiving concomitant antipsychotics. Additional signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, treatment should be discontinued.

 

Advice for Healthcare Professionals

  • Rhabdomyolysis has been reported very rarely in patients treated with donepezil and has occurred independently of NMS and in close temporal association with donepezil initiation or dose increase.
  • Patients and carers should be made aware of and advised to immediately report any signs or symptoms of rhabdomyolysis experienced (e.g. muscle weakness, tenderness or pain particularly, if at the same time, they feel unwell, have a high temperature or have dark urine.)
  • The product information for donepezil (Summary of Product Characteristics (SmPC) and Package Leaflet (PL)) will be updated accordingly shortly.

 

Key message

  • Rhabdomyolysis has been reported very rarely in patients treated with donepezil and has occurred independently of NMS and in close temporal association with donepezil initiation or dose increase.
  • Patients and carers should be alerted to signs and symptoms of these conditions and told to inform their doctor immediately if any experienced.

 

*Brands include Aricept, Donesyn, Dozept, Donecept. See www.hpra.ie for further details.

Caroline McDermott

Type 2 Diabetes and Insulin Therapy – ADA-EASD Guidelines 2015

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Download PDF

Key Recommendations on Management of Type 2 Diabetes

  • Individualise glycaemic targets and glucose-lowering therapies.
  • Diet, exercise, and education remain the foundation of all type 2 diabetes treatment programmes.
  • Metformin is the optimal first-line drug in the absence of contraindications.
  • After metformin, it is reasonable to consider combination therapy with an additional 1-2 oral or injectable agents with the objective of minimising side-effects where possible.
  • For many patients insulin therapy alone or in combination with other agents will ultimately be required to maintain glucose control.
  • All treatment decisions, where possible, should take into account the patient’s preferences, needs and values.
  • A major focus of therapy must be comprehensive cardiovascular risk reduction.

 

Diagnosis of Type 2 Diabetes

Diabetes may be diagnosed based on HbA1c criteria or plasma glucose criteria, either the fasting plasma glucose (FPG) or the 2-h plasma glucose (2-h PG) value after a 75-g oral glucose tolerance test (OGTT). Diabetes may be identified in seemingly low risk individuals who happen to have glucose testing, in symptomatic patients, and in higher-risk individuals who are tested because of a suspicion of diabetes.

 

Table 1. Criteria for Diagnosis of Type 2 Diabetes

Table 1 Criteria for Diagnosis of Type 2 Diabetes

 

Testing for Diabetes or Prediabetes in Asymptomatic Adults

Consider testing in all adults who are overweight (BMI≥25kg/m2 or ≥23 kg/m2 in Asian Americans) and have ≥1 risk factor:

  • Physical inactivity
  • First-degree relative with diabetes
  • High-risk race/ethnicity
  • Women who delivered a baby weighing >9lb or were diagnosed with gestational diabetes mellitus
  • Hypertension (≥140/90mmHg or on therapy for hypertension)
  • HDL cholesterol level <35mg/dL (0.90mmol/L) and/or a triglyceride level >250mg/Dl (2.82mmol/L)
  • Women with polycystic ovary syndrome
  • HbA1c ≥5.7%, IGT, or IFG on previous testing
  • Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans)
  • History of cardiovascular disease

 

For all patients, particularly those who are overweight or obese, testing should begin at age 45 years. If results are normal, testing should be repeated at a minimum of 3 year intervals, with consideration of more frequent testing depending on initial results (e.g., those with prediabetes should be tested yearly) and risk status.

 

Table 2. Glycaemic Targets for Non-pregnant Adults with Diabetes

Table 2 Glycaemic Targets for Non-Pregnant Adults with Diabetes

Click on image to enlarge

 

Assessment of Glycaemic Control

Two primary techniques are available to assess the effectiveness of glycaemic control: Patient self-monitoring of blood glucose (SMBG) or interstitial glucose and A1C. Continuous glucose monitoring (CGM) may be a useful adjunct to SMBG in selected patients. SMBG results may help guide treatment decisions and/or self-management for patients using less frequent insulin injections or noninsulin therapies. CGM may be a supplemental tool to SMBG in those with hypoglycaemia unawareness and/or frequent hypoglycaemic episodes.

 

Patients on multiple-dose insulin or insulin pump therapy should perform SMBG prior to meals and snacks, occasionally postprandially, at bedtime, prior to exercise, when they suspect low blood glucose, after treating low blood glucose until they are normoglycaemic, and prior to critical tasks such as driving.

 

Multiple Agents Needed for Most People with Diabetes

Initial therapy: Most patients should begin with lifestyle changes – healthy eating, weight control, increased physical activity, and diabetes education. When lifestyle efforts alone have not achieved or maintained glycemic goals, metformin monotherapy should be added at, or soon after, diagnosis (in patients intolerant, or with contraindications for, metformin, select initial drug from other treatment options).

 

Advancing to dual combination therapy: If the HbA1c target is not achieved after ~3 months with metformin, there are six drug choices including a second oral agent (sulfonylurea, TZD, DPP-4 inhibitor, or SGLT2 inhibitor), a GLP-1 receptor agonist, or basal insulin. The higher the HbA1c, the more likely insulin will be required. Shared decision making with the patient is important to help in the selection of therapeutic option. The choice is based on patient and drug characteristics, with the over-riding goal of improving glycaemic control while minimising side-effects. Consider beginning at this stage when HbA1c ≥9%.

 

Advancing to triple combination therapy: Evidence suggests that there is some advantage in adding a third noninsulin agent to a two-drug combination not achieving the glycaemic target. However, the most robust response will usually be with insulin. Since diabetes is associated with progressive beta-cell loss, many patients, especially those with long-standing disease, will ultimately need to be transitioned to insulin. Insulin should be preferred in circumstances where the degree of hyperglycaemia (e.g. ≥8.5%) makes it unlikely that another drug will be sufficiently effective. In using triple combinations the essential consideration is obviously to use agents with complementary mechanisms of action.

 

Combination injectable therapy: If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables; (2) on GLP-1 RA, add basal insulin; or (3) on optimally titrated basal insulin, add GLP-1 RA or mealtime insulin. In refractory patients consider adding thiazolidinedione or SGLT2 inhibitor. Consider beginning at this stage when blood glucose is 16.7 – 19.4mmol/L and/or HbA1c ≥10 – 12%, especially if symptomatic or catabolic features are present.

 

Figure 1. Overview of Approach to Starting and Adjusting Insulin in Type 2 Diabetes (Sequential Insulin Strategies)

Figure 1 Overview of Approach to Starting and Adjusting Insulin in Type 2 Diabetes

Click on image to enlarge

 

Table 3. Different Types of Insulins Available in Ireland

Table 3 Different Types of Insulins Available in Ireland

Click on image to enlarge

 

Abbreviations:

HbA1c, glycated haemoglobin; FBG, fasting blood glucose; OGTT, oral glucose tolerance test; SMBG, self-monitoring of blood glucose; CGM, continuous glucose monitoring; TZD, thiazolidinedione; DPP-4, dipeptidyl peptidase-4; SGLT2, sodium glucose co-transporter 2; GLP-1-RA, glucagon-like peptide-1 receptor agonist; GLP-1 receptor agonist; hypo, hypoglycemia; PPG, postprandial glucose

 

References:

1. Inzucchi SE et al. Management of hyperglycemia in type 2 diabetes 2015: a patient-centered approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015;38:140-149 [adapted].

2. Inzucchi SE et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2012;35:1364-1379 [adapted]

Caroline McDermott


Fluanxol Discontinued

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Lundbeck Ireland Ltd. would like to inform you that Fluanxol (flupentixol dihydrochloride) 0.5mg and 1mg film-coated tablets were discontinued from 1st October 2015 due to low sales and resulting supply issues. Existing product in the supply chain will be sold until stocks are exhausted. Please be advised that no therapeutic alternatives will remain on the market. If you require any further information, please contact Lundbeck Ireland Ltd. on (01) 4689 800.

Tara Sweeney

Kadcyla ▼

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Company: Roche Products (Ireland) Ltd.

Legal category: Prescription. Sport permitted.

Active ingredient: Trastuzumab emtansine 100mg, 160mg.

Description: Powder concentrate for solution for infusion.

Presentation: Price available on application.

Indication: As a single agent, for treatment of HER2-positive, unresectable locally advanced or metastatic breast cancer, previously treated with trastuzumab and a taxane, separately or in combination. Patients should have either received prior therapy for locally advanced or metastatic disease, or developed disease recurrence during or within six months of completing adjuvant therapy.

Pharmacology: Trastuzumab emtansine is a HER2-targeted antibody-drug conjugate which contains the humanised anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitor DM1 via the stable thioether linker MCC. Emtansine refers to the MCC-DM1 complex. Conjugation of DM1 to trastuzumab confers selectivity of the cytotoxic agent for HER2-overexpressing tumour cells, thereby increasing intracellular delivery of DM1 directly to malignant cells. Upon binding to HER2, trastuzumab emtansine undergoes receptor-mediated internalisation and subsequent lysosomal degradation, resulting in release of DM1-containing cytotoxic catabolites.

Dosage: Adult: 3.6mg/kg bodyweight by intravenous infusion every 3 weeks. Administer first dose as 90 minute infusion. If well tolerated, can administer subsequent doses as 30 minute infusions. Observe patients closely during and for at least 90 minutes after first infusion, and during and for at least 30 minutes after subsequent infusions, for infusion-related reactions (IRRs); slow or interrupt infusion rate if reactions develop. See SPC for dose reduction schedule and for dose modifications for the following adverse reactions: Increased transaminases, hyperbilirubinemia, thrombocytopenia, left ventricular dysfunction. Do not re-escalate dose after it has been reduced. Duration: Continue until disease progression or unacceptable toxicity. Elderly: ≥75 years, limited data. Children: Under 18 years, no relevant use.

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Pregnancy, lactation. Patients should use effective contraception (including male patients or their female partners) and women should not breast feed during therapy and for 7 months following last dose.

Special precautions: Do not administer as an intravenous push or bolus. Life-threatening infusion reactions (permanently discontinue). Suspend if Grade 3 or 4 peripheral neuropathy occurs until resolution to ≤Grade 2. Severe renal impairment (monitor carefully). Interstitial lung disease including pneumonitis (discontinue permanently; patients with dyspnoea at rest due to complications of advanced malignancy and co-morbidities may be at increased risk). Monitor liver function prior to initiation and each dose. Hepatotoxicity (asymptomatic increases in serum transaminases) and serious hepatobiliary disorders, including nodular regenerative hyperplasia (NRH) of the liver, observed. Discontinue permanently if NRH, or serum transaminases >3xULN and concomitant total bilirubin >2x ULN, occur. Test cardiac function prior to initiation and at regular intervals (e.g. every three months) during treatment. Left ventricular ejection fraction (LVEF) <40% observed. Risk factors for a cardiac event include advancing age (>50 years), low baseline LVEF values (<55%), low LVEF levels prior to or following use of paclitaxel in adjuvant setting, prior or concomitant use of antihypertensives, previous therapy with an anthracycline and high BMI (>25kg/m2). Not recommended: Use in patients who had trastuzumab permanently discontinued due to IRRs or hypersensitivity. Thrombocytopenia, and cases of bleeding events with a fatal outcome, observed. Monitor platelet counts prior to each dose. Monitor patients with thrombocytopenia (≤100,000/mm3) and patients on anti-coagulants closely. If platelet count decreases to Grade 3 or greater (<50,000/mm3), do not administer until platelet counts recover to Grade 1 (≥75,000/mm3). Driving/using machines (IRRs).

Drug interactions: Avoid: Strong CYP3A4 inhibitors.

Adverse drug reactions: Urinary tract infection, thrombocytopenia, anaemia, neutropenia, leucopoenia, hypokalaemia, insomnia, peripheral neuropathy, peripheral oedema, headache, dizziness, dysgeusia, memory impairment, haemorrhage, hypertension, epistaxis, cough, dyspnoea, GI upset, rash, pruritus, alopecia, nail disorder, Palmar-plantar erythrodysaesthesia syndrome, urticaria, musculoskeletal pain, arthralgia, myalgia, fatigue, pyrexia, chills, increased transaminases, increased blood alkaline phosphatase, drug hypersensitivity, dry eye, conjunctivitis, blurred vision, increased lacrimation, left ventricular dysfunction, IRRs.

Full prescribing information and references available from Roche Products (Ireland) Ltd. Telephone: (01) 4690700.

Tara Sweeney

Gazyvaro ▼

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W-Gazyvaro

Company: Roche Products (Ireland) Ltd.

Legal category: Prescription. Hospital only. Sport permitted.

Active ingredient: Obinutuzumab 1000mg.

Description: Concentrate for solution for infusion.

Presentation: 40ml vial-1. Price on request.

Indications: In combination with chlorambucil for treatment of adult patients with previously untreated chronic lymphocytic leukaemia and with comorbidities making them unsuitable for full-dose fludarabine based therapy.

Pharmacology: Obinutuzumab is a recombinant monoclonal humanised and glycoengineered Type II anti-CD20 antibody of the IgG1 isotype. It specifically targets the extracellular loop of the CD20 transmembrane antigen on the surface of non-malignant and malignant pre-B and mature B-lymphocytes. It induces direct cell death and mediates antibody dependent cellular cytotoxicity and antibody dependent cellular phagocytosis through recruitment of FcγRIII positive immune effector cells and it mediates a low degree of complement dependent cytotoxicity. It mediates potent B-cell depletion and antitumour efficacy.

Dosage: Adult: Prophylaxis and premedication for tumour lysis syndrome (TLS) or infusion related reactions (IRRs): See SPC. Six 28 day treatment cycles. Cycle 1: Day 1, 100mg; day 2 (or day 1 continued), 900mg; day 8, 1000mg; day 15, 1000mg. Cycles 2-6: Day 1, 1000mg. Infusion rate: See SPC. Elderly: As per adults. Children: Under 18 years, not recommended.

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Pregnancy (assess risk/benefit), lactation. Women must use effective contraception and not breastfeed during and for 18 months after treatment.

Special precautions: Intravenous use only; do not administer as an intravenous push or bolus. Correct infections before initiation. Closely monitor for thrombocytopenia (especially during first cycle). Caution: Hepatitis B carriers (screen before initiation in all patients, hepatitis B virus reactivation with fatal results can occur, do not use in patients with active hepatitis B disease), pre-existing cardiac/ pulmonary conditions, history of recurring/ chronic infections (fatal infections reported), history of cardiac disease. May occur: IRRs (permanently discontinue if life-threatening or second occurrence of severe IRR occurs), hypersensitivity reactions (permanently discontinue if suspected), tumour lysis syndrome, neutropenia (closely monitor if occurs), progressive multifocal leukoencephalopathy (permanently discontinue if confirmed). Cytokine release syndrome cases reported. Hepatic impairment, severe renal impairment; safety and efficacy not established. Driving/using machines (if IRRs present).

Drug interactions: Live vaccines (not recommended). Concomitant platelet inhibitors and anticoagulants can worsen thrombocytopenia.

Adverse drug reactions: Urinary tract infection, nasopharyngitis, oral herpes, rhinitis, pharyngitis, squamous cell carcinoma of skin, neutropenia, thrombocytopenia, anaemia, leukopenia, TLS, hyperuricaemia, atrial fibrillation, hypertension, cough, gastrointestinal upset, alopecia, arthralgia, back pain, musculoskeletal chest pain, pyrexia, decreased white blood cell count, decreased neutrophil count, increased weight, IRRs.

Full prescribing information and references available from Roche Products (Ireland) Ltd. Telephone: (01) 4690700.

Tara Sweeney

Abasaglar ▼

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W-Abasaglar

Company: Eli Lilly and Co (Ireland) Ltd.

Legal category: Prescription. GMS reimbursable. Sport prohibited.

Active ingredient: Insulin glargine 100 units/ml.

Description: Solution for injection.

Presentation: 5 x 3ml cartridges, €45.80; 5 x 3ml KwikPen, €45.80.

Indications: Treatment of diabetes mellitus.

Pharmacology: Insulin glargine is a human insulin analogue with low solubility at neutral pH. After injection into subcutaneous tissue, acidic solution is neutralised leading to formation of microprecipitates from which small amounts of insulin glargine are continuously released, providing a smooth, peakless, predictable concentration/time profile with a prolonged duration of action.

Dosage: Adult: Administer subcutaneously once daily at the same time each day. Adjust dose individually. Can be given with orally active antidiabetics in type 2 patients. Units are not interchangeable with IU or other insulin analogue units. Elderly: As per adults. Children: 2 years and older, as per adults. Under 2 years, not recommended.

Contraindications: Hypersensitivity to the active substance or to any of the excipients.

Special precautions: Not for diabetic ketoacidosis. Do not administer by intravenous injection. Caution: Significant stenoses of coronary arteries or of blood vessels supplying the brain, proliferative retinopathy. Hepatic/ renal impairment, insufficient glucose control, tendency to hyper- or hypoglycaemic episodes. Transition from other insulins requires strict medical supervision (may require dose adjustment). Closely monitor where warnings signs of hypoglycaemia are reduced, e.g. markedly improved glycaemic control, gradual development of hypoglycaemia, elderly, transfer from animal insulin to human insulin, autonomic neuropathy, long history of diabetes, psychiatric illness. Closely monitor factors increasing susceptibility to hypoglycaemia (may require dose adjustment), e.g. change in injection area, improved insulin sensitivity, unaccustomed/ increased/ prolonged physical activity, intercurrent illness (requires intensified metabolic monitoring), inadequate food intake, missed meals, certain uncompensated endocrine disorders. Normal or decreased values for glycated haemoglobin (consider possibility of recurrent, unrecognised (especially nocturnal) episodes of hypoglycaemia). Driving/using machines (avoid hypoglycaemia). Pregnancy.

Drug interactions: Caution: Pioglitazone (patients with cardiac heart failure risk factors). Substances that may enhance the blood-glucose-lowering effect include oral antidiabetics, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, propoxyphene, salicylates, somatostatin anologues, sulphonamides. Substances that may reduce the blood-glucose-lowering effect include corticosteroids, danazol, diazoxide, diuretics, glucagon, isoniazid, oestrogen, progestogen, phenothiazine derivatives, somatropin, sympathomimetics, thyroid hormones, atypical antipsychotics, protease inhibitors, beta-blockers, clonidine, lithium salts, alcohol, pentamidine, guanethidine, reserpine.

Adverse drug reactions: Hypoglycaemia, lipohypertrophy, injection site reactions.

Full prescribing information and references available from Eli Lilly and Co (Ireland) Ltd. Telephone: +353 1 664 0446.
E-mail: ukmedinfo@lilly.com.

Tara Sweeney

The starting dose of thalidomide should be reduced when combined with melphalan in patients over 75 years

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Thalidomide is licensed for use across the EU since 2008, in combination with melphalan and prednisone as first-line treatment for patients with untreated multiple myeloma who are aged 65 years or older, or those who are ineligible for high-dose chemotherapy. Thalidomide is an immunomodulatory agent, who has antineoplastic, antiangiogenic and proerythropoietic properties.

 

Safety results from a phase 3 study1, the results of which were supported by another study2, have highlighted a new important recommendation of a reduced initial dose of thalidomide when combined with melphalan and prednisone in patients >75 years of age with untreated multiple myeloma. The adverse reaction profile reported in patients >75 years of age treated with thalidomide 100mg daily was similar to the adverse reaction profile observed in patients ≤75 years of age treated with thalidomide 200mg once daily. However patients aged >75 years are potentially at risk for a higher frequency of serious adverse reactions. Therefore:

 

Advice to Healthcare Professionals

  • 100mg/day starting dose is now recommended in patients >75 years of age.
  • When combined with thalidomide, a reduced starting dose of melphalan should be used in patients >75 years of age.
  • Patients aged >75 years are potentially at risk for a higher frequency of serious adverse reactions and should be monitored carefully.

 

Key message

  • There is an increased risk of serious adverse reactions in patients aged over 75 years.
  • Therefore a 100mg/day starting dose of thalidomide is now recommended in patients in this age group.
  • A reduced starting dose of melphalan should be used in patients concomitantly taking thalidomide aged over 75 years.
  • The product information (i.e. Summary of Product Characteristics (SmPC) and package leaflet (PL)) will be updated shortly to include this information. A Direct Healthcare Professional Communication (DHPC) has been circulated by the Marketing Authorisation Holder (MAH) to the relevant healthcare professionals and is available from the HPRA website (www.hpra.ie).

 

*Further details on Thalidomide Celgene is available on www.hpra.ie and www.ema.europa.eu

 

References

1. Study MM-020 – Phase 3, multicenter, randomized, open-label, 3-arm study to determine the efficacy and safety of lenalidomide plus low-dose dexamethasone when given until progressive disease or for 18 four-week cycles versus the combination of melphalan, prednisone, and thalidomide given for 12 six-week cycles in newly diagnosed MM subjects either ≥65 years or not candidates for stem cell transplant.

2. Study IFM 01/01 – Comparison of Melphalan-Prednisone (MP) to MP Plus Thalidomide in the Treatment of Newly Diagnosed Very Elderly Patients (>75 Years) With Multiple Myeloma.

Caroline McDermott

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