Implications of altering oral solid-dose formulations

The crushing of tablets or the opening of capsules – by both patients and healthcare professionals – remains a common response in cases where patients need their medicines and there are no alternative formulations available^{16 66 67 68 69 70 71 72 73}. For cost reasons, several UK guidelines^{47 75} suggest that “using a licensed medicine in an unlicensed manner, for example by dispersing tablets in water or by opening capsules” should be considered before using a ‘Special’. Others state that “altering a solid-dose formulation should be reserved as last-resort”⁴⁶.

What is clear however, and consistent across guidance, is that the potential consequences of manipulating a medicinal product are manifold and should only be undertaken after giving full consideration to the risks and seeking appropriate expert advice.

The Royal Pharmaceutical Society states that changing the way in which a dosage form is presented can alter its absorption characteristics, result in medicines instability, produce local irritant effects, cause failure to reach the site of action, may produce occupational health and safety issues, and could result in a preparation with an unacceptable taste⁷⁶.

These risks are starkly illustrated by a case in which a crushed extended-release nifedipine tablet contributed to a patient fatality⁷⁷. In this instance the administration of a crushed nifedipine XL tablet resulted in severe hypotension and the concurrent administration of labetalol prevented a compensatory heart rate increase in the patient. Yet despite the well documented risks presented by altering certain solid-dose formulations – notably modified release dosage forms and enteric coated tablets – a survey in the United States found that 21% of critical care nurses (n=1167) reported routinely crushing and administering enteric-coated medications through feeding tubes. Similarly 15% reported routinely crushing sustained-release medications⁶⁷.

As with the preparation of ‘Specials’, the crushing or splitting of oral dosage forms constitutes an unlicensed use of the medicine (unless this form of manipulation is covered by the product’s Marketing Authorisation) and the decision to do so should be documented in the patient’s notes. It brings additional responsibilities and liabilities for the prescriber, the supervising pharmacist and any other healthcare professionals involved in the preparation and/or administration of the medicine. In particular, the Consumer Protection Act makes the producer of a product responsible, or ‘strictly liable’, for any harm caused by a defective product. When tablets are crushed for a prescription the manufacturer is not responsible for any harm resulting as the product is now dispensed in an unlicensed form; responsibility is now held by the person (and associated healthcare professionals) who altered the medication.

The prescriber must also take into account the patient’s swallowing / feeding status and their ability to administer medicines in this way.

Most important is the potential for increased risk to the patient. In this instance therefore, healthcare professionals should be fully aware of recommended best practice and the potential consequences of dose manipulation⁷⁶:

Risks to healthcare workers and carers

Crushing products with carcinogenic (e.g. tamoxifen; methotrexate) or teratogenic (e.g. valganciclovir) potential may expose carers or healthcare professionals to health risks through powder aerosolisation and as such should not be undertaken. Similarly, preparations containing hormones (oral contraceptives; hormonal replacement therapy), corticosteroids (such as dexamethasone) and some other drugs (finasteride; mycophenolate) should not be crushed due to the risks associated with powder aerosolisation^{46 78 79 80}. In addition several drug substances may also cause irritation if the powder is aerosolised and inhaled or comes into contact with the eyes, skin, or other mucous membranes e.g. alendronate, diflunisal, isotretinoin, piroxicam, ganciclovir, hydroxycarbamide powder.

Drug instability

If an enteric coating, which protects a drug from the acidic environment in the stomach, is removed by crushing the tablet, the in vivo drug degradation will increase, adversely impacting on the drug’s clinical effectiveness. Coatings can also be added to protect the drug from the effects of light, eg. nifedipine.

Changes in pharmacokinetics & bioavailability

Splitting or crushing oral dosage forms may produce changes in the drug pharmacokinetics and bioavailability resulting in under-dosing or conversely, adverse effects. Such changes may be particularly important for drugs that have narrow therapeutic windows e.g. phenytoin, digoxin, carbamazepine, theophylline, or sodium valproate⁴⁶.

Drug irritation

Many drugs have irritant actions and are formulated or coated to minimise the risk to patients. Some medications may cause oesophageal or stomach irritation or ulceration if they are crushed or opened (e.g. nitrofurantoin, potassium chloride, alendronate, diclofenac).

Bitter tasting drugs

For drugs which have a particularly bitter taste, a coating (sugar/film) is often used to help mask the taste of the active substance. Examples include ibuprofen, quinine, cefuroxime axetil, ciprofloxacin, docusate, pseudoephedrine and praziquantel. Crushing such tablets may produce a preparation which is unpleasant to taste and which a patient may refuse to take.

Requirement for patient monitoring

Blood pressure monitoring has been advised when crushed preparations of alfuzosin, carvedilol, isosorbide mononitrate, ramipril or valsartan are administered due to the risk of hypotensive effects⁸¹. If oral dosage forms of glibenclamide, gliclazide, or metformin are crushed or opened, monitoring of blood glucose levels has been suggested⁸¹.

Extended release preparations

Extended-release products are formulated to release the drug over an extended period of time, generally over 12 to 24 hours. Crushing an extended-release preparation may change the drug release characteristics with the potential for an unintended large bolus dose being delivered rather than controlled release over the intended timescale. The consequence of this would be for a potentially toxic dose of medication to be delivered upon administration with an increased risk of adverse effects. Conversely, while there is the risk of initial overdosing, there will also be under dosing at later times which could result in a lack of clinical efficacy^{82 83}.

Extended-release formulations often have one of the following abbreviations after the product name CR, ER, LA, SR, XL or XR.

Several different methods are used to modify the rate of release of a drug:

• Modifying the pharmaceutical form – increasing the drug particle size or forming insoluble crystals leads to a reduced rate of drug release e.g. Tegretol Retard, Adalat Retard.
• Coating pellets – coating drug pellets with a slowly dissolving polymer can vary the drug release rate e.g. Slo-Phyllin, Inderal-LA.
• Insoluble matrix – drug is dispersed within an insoluble matrix and as fluid enters the matrix, the drug is dissolved and slowly diffuses out e.g. Slow-K, Imdur Durules.
• Eroding matrix – the drug is dispersed within a soluble matrix and as the matrix is slowly eroded the drug is released e.g. MST Continus, Phyllocontin Continus.
• Osmotic pump – the drug and an osmotic agent are enclosed in a semi-permeable membrane; water is drawn into the matrix and the dissolved drug is released through a laser drilled hole e.g. Adalat LA.

Enteric coated preparations

Enteric coatings on tablets are polymers that remain intact in the stomach but dissolve and release the drug in the more alkaline pH of the small intestine. Enteric coatings are applied to tablets to delay the release of drugs that are inactivated by the stomach contents (pancreatin; erythromycin; omeprazole), to prevent stomach irritation (aspirin; diclofenac; naproxen; corticosteroids), or to delay the onset of action to a specific site within the gastrointestinal tract (sulphasalazine in the treatment of Crohn’s disease). Crushing enteric coated tablets may result in the drug being released too early, destroyed by stomach acid, or irritating the stomach lining. In general, manipulation of enteric coated and extended-release formulations is not recommended.

Other types of dosage forms

Sublingual and buccal tablets allow a drug substance to be directly absorbed across the mucosal membrane leading to rapid rises in the blood concentration and avoiding first pass metabolism in the liver. Lozenges are large tablets that are intended to stay in the mouth for periods of 10 to 15 minutes while they dissolve and have a local action in the mouth. If these types of dosage form are crushed, the pharmacokinetics and bioavailability of buccal and sublingual products will be altered, and the local action of lozenges will be affected.

Soluble or dispersible tablets

Some tablets however, can be dispersed in a small volume of water (~ 10mL) within a few minutes. Assuming that this is done immediately prior to administration to patients, drug stability is not usually a major issue. (Slow or modified-release preparations must not be used in this manner.) This practice also presents fewer health and safety risks than crushing tablets which can expose the carer to potentially harmful dusts via inhalation.

However, if only part of the liquid containing the dispersed tablet is administered to a patient, problems can arise with drugs that are insoluble in aqueous vehicles⁸⁴. Aggregation, sedimentation and precipitation of insoluble drugs can result in poor accuracy of the dose administrated. For this reason, tablet dispersion may not be a practical option in paediatrics.

As illustrated by the following case study, problems can be exacerbated when patients are transferred from secondary care to primary care with incomplete prescribing information. A 4kg neonate was discharged from hospital on phenobarbital 20mg three times a day (tds) prescribed as 2ml tds of 50mg/5ml alcohol-free phenobarbital suspension. Upon repeat prescription, the GP prescribed a British Pharmacopoeia (BP) suspension of 15mg/5ml – as per the general practice prescribing system – which the pharmacy dispensed as 6.8ml (20mg) tds. Four days later, the child was admitted to hospital with lethargy and increased fitting. The 15mg/5ml preparation contained 38% alcohol and the volume of 6.8ml administered was similar to giving the neonate a glass of wine three times a day. A simple specification on the prescription that the suspension should be ‘alcohol-free’ would have prevented this ⁸⁵.