What you need to know about fixed-dose combinations

• A large number of factors contribute to non-adherence.⁶
  Do not choose FDC therapy solely based on the possibility of improved adherence, convenience or cost advantages of the preparation.
• Evidence for improved adherence with combination products is strongest when the reduction in pill burden is greatest.^5,7
  Assess the level of complexity involved in a patient's medicine regimen before choosing FDC therapy.
• Be alert to unintended double- or under-dosing at the time of switching and discuss this with the patient.
  Show patients which medicines are being replaced by the combination product. Encourage them to use and maintain a Medicines List to keep track of the active ingredients as well as the brand names of their medicines.
• Identify which component(s) in an FDC are responsible for adverse effects if they occur.
  Watch for signs and symptoms specific to individual components.
• It is best to start and stabilise patients on the individual components before starting the corresponding FDC product.⁸
  This facilitates adjustment of dose based on response and monitoring of adverse effects.
• Patients taking FDC products may be eligible for a Home Medicines Review.
  Identify patients at risk of medicines-related problems:
  • those taking five or more regular medicines
  • those taking more than 12 doses of medicine a day
  • those who have had a significant change to their medicine regimen in the past 3 months or symptoms of an adverse drug reaction.⁹

Combination medicines (or fixed-dose combination [FDC] medicines) are:

• medicines containing two or more active components in fixed proportions in a single dosage form
  
• several medications in fixed combination to be taken together, presented in composite packaging (co-pack).⁶
  

FDC product examples¹⁰

Adherence with medication regimens can influence the achievement of health outcomes for:⁶

• communicable diseases such as HIV or tuberculosis (TB), when irregular treatment over a short period causes drug resistance affecting treatment options for individual patients and constitutes a public health problem.^7,11 Evidence for improved adherence with combination products is strongest when the reduction in pill burden is greatest.⁷ The availability of FDCs of common HIV and TB medicines effectively reduces the (considerable) pill burdens and improves adherence.^7,12
  
• other chronic diseases such as hypercholesterolaemia. There have been serious outcomes associated with non-adherence such as increased cardiac events¹³ and cardiovascular morbidity and mortality.^14,15 A systematic review of FDC formulations for diabetes reported 10% to 13% improved adherence (although one included trial reported no adherence advantage), improved satisfaction and lower medical costs.¹⁶
  

One meta-analysis of people taking medicines for HIV, hypertension, tuberculosis and diabetes estimated that FDC preparations reduced the risk of non-adherence by about 25%.⁴

While combining medicines into a simplified dosing regimen is associated with a significant improvement in adherence,2-4 use of combination products does not by itself ensure improved adherence in every individual, as many factors contribute to non-adherence.⁶

There is limited evidence that FDCs are better than other dosing aids. Although one systematic review concluded that both FDC and dosing aids improved adherence it was noted that the quality and quantity of the studies performed in this area was poor.¹⁷

To date, improved adherence with co-packs has not been directly demonstrated. There is some evidence to show that reminder packaging, normally included in co-packs, improves clinical targets such as blood pressure.¹⁸ However, more research is needed to fully understand the effect of reminder packaging.¹⁸

A recent systematic review of interventions to improve adherence to lipid-lowering medicine concluded that labour-intensive adherence interventions were more effective than simplifying the drug regimen.¹⁹

Prescribing data indicate an increasing preference for FDC products even when guidelines and PBS-listing restrictions require a single agent as first line. At its meeting in February 2013 DUSC prioritised for review cardiovascular system and anti-glaucoma FDC products.¹

FDC antihypertensives should be reserved for use when initial management with a single antihypertensive is ineffective.²⁰ However, a study in an Australian veteran population assessed the use of four FDC antihypertensive medicines and found only a small number of patients had been dispensed corresponding individual medicines 12 months before starting the FDC products.²¹

Immediately before starting the FDC, fewer than 1% of people were taking each individual medicine, 29% were taking one of the individual medicines, 58% were taking antihypertensive medicines other than the individual ones in the FDC, and 12% were receiving no antihypertensive therapy.²¹

A study of prescribing of anti-diabetic agents in an Australian veteran population demonstrated a higher-than-expected prescribing of metformin–glitazone FDC combinations despite guidelines recommending metformin as first-line therapy followed by addition of a sulfonylurea if patients were not adequately controlled.⁸ This study found that:

• around 22% of veterans with diabetes were prescribed this FDC product without any prior use of constituent agents or a sulfonylurea
  
• 57% of FDC initiations occurred after a step-up from metformin alone; however, the PBS listing at the time only permitted use when metformin therapy alone failed and a sulfonylurea was contraindicated
  
• only 30% of initiations occurred after patients had been treated with metformin and rosiglitazone as separate products
  
• 10% of patients started on the FDC product also received concurrent prescriptions for metformin, suggesting that either:
   - dose escalations were required to achieve adequate control that could not be achieved using the FDC, in which case the FDC failed to fulfil its primary purpose to reduce pill burden, or
   - inadvertent duplication of FDC and single-agent prescriptions was occurring.

In 2011 a DUSC review indicated a very high rate of children being started with an FDC of inhaled corticosteroids (ICS) and inhaled long-acting beta-2 agonists (LABAs) without prior use of a single-ingredient inhaler, as recommended by guidelines.²²

This followed an earlier finding that 40% of children were supplied with an FDC product without being prescribed an earlier single-ingredient ICS.²²

Combination ICS–LABA inhalers should not be used as a first-line preventer for persistent asthma in children because of the ongoing concerns about the side-effects.²³

A postmarket review of starting asthma medicines in children is being undertaken.²² DUSC recognised this is a complex area of treatment and further clarification of the issues surrounding asthma management in children is needed.²²

Some adverse effects are common to many active ingredients so it may be difficult to identify which medicine is responsible. Watch for signs and symptoms specific to individual components.

Adverse effects are often overlooked in older people because associated signs and symptoms may be confused with underlying disease or normal ageing.24 Sometimes the only way to know whether a symptom is a side effect is to temporarily stop the medicine and see if the symptoms improve.²⁵

Make sure patients are aware that if they develop adverse effects to the FDC (which requires them to stop the FDC) they will most likely need to restart one of its components.

Patients taking FDC products may be eligible for a Home Medicines Review if they are taking more than 12 doses of medicine a day, have had a significant change to their medicine regimen in the past 3 months or have symptoms of an adverse drug reaction.⁹

In some situations it is best to start and stabilise patients on individual tablets before starting the corresponding FDC product.²⁶ If patients start treatment using FDC products, ensure that the relatively inflexible dosing of FDCs is compatible with their requirements.

Dose adjustment of individual active ingredients is required in some situations:

• older patients: for example, the metformin–glibenclamide FDC product may cause hypoglycaemia if patients taking it have not previously been stabilised on a longer-acting sulfonylurea²⁶
  
• patients with kidney impairment: for example, the sitagliptin–simvastatin FDC product does not provide an option for dose adjustment of the sitagliptin component (lower doses are required in this population).²⁷