Suspected adverse reaction to compounded preparations prescribed for weight loss: two cases of cerebral venous thrombosis

Abstract

We report two cases of cerebral venous thrombosis associated with the use of compounded preparations containing several active substances prescribed for weight loss. In both cases there is suspicion of additive/synergic interaction with oral contraceptives. The adverse drug reactions were considered serious, being life-threatening and causing hospitalisation for days.

Background

Cerebral venous thrombosis (CVT) is an uncommon cerebrovascular disease with an annual incidence from 0.22 to 1.57 per 100.00.^1–3 CVT is three times more frequent in women than in men and several risk factors for CVT have been identified: some are general risk factors for venous thromboembolism (VTE) such as hereditary thrombophilia, use of oral contraceptives, cancer, pregnancy and puerperium, and others are specific risk factors to CVT, such as head injury, dural arteriovenous fistula, head and neck infections, spontaneous intracranial hypotension and dehydration.^{1 4–7} Very well-established pharmacological risk factors for CVT are oral contraception and hormone replacement therapy^{4 8}; conversely CVT has sporadically been reported as adverse drug reaction (ADR) with other drugs such as anabolic androgenic steroids, corticosteroids, erythropoietin, sildenafil, l-asparaginase and dexamethasone among others.^9–15 Within illicit drugs, CVT has been reported to be related to cocaine use.¹⁶

Clinical manifestations of CVT result from the decrease in cerebrospinal fluid absorption and cerebral blood drainage, leading to increased intracranial pressure, venous infarct and intracerebral haemorrhage. The most frequent presentations are intracranial hypertension syndrome (headache, papilledema and visual complaints), focal deficits, seizures and encephalopathy.^{2 17 18} Atypical presentations include cavernous sinus syndrome, subarachnoid haemorrhage and multiple cranial neuropathies. In the cases presenting as intracranial hypertension syndrome, the most important alternative diagnoses to consider are intracranial mass lesions, meningitis and idiopathic intracranial hypertension. When a focal deficit or seizure is the initial presentation, the alternative diagnosis can be ischaemic or haemorrhagic stroke, central nervous system infection and tumour. Diagnosis is usually confirmed by CT or MRI with venography.¹ Anticoagulation is the recommended treatment. Certain patients can benefit from measures to reduce intracranial pressure, such as decompressive craniectomy.¹⁹ Usually CVT has a favourable prognosis, although death can occur in approximately 5% of the patients in the acute phase and the recurrence risk is approximately 2%–4%.^{20 21}

Compounded preparations are pharmaceutical products prepared and dispensed under the responsibility of a pharmacist in their two different forms as Magistral Formula or Officinal preparation and are intended to fulfil particular patient’s needs in specific situations in which available proprietary medicines do not meet the specific requirements. Typically, they are adopted to circumvent the lack of paediatric formulations or whenever there is a specific need for alternative dosage forms or different excipients/raw materials and often to prepare special combinations of different active substances; exceptional circumstance where compounding is used is the case of stock breakages due to market and industrial production reasons. Besides efficacy, quality and safety of compounded medicines are not guaranteed as these medicines are exempt from marketing authorisation and are considered as unapproved or unlicensed medicines by the regulatory agencies.^{22 23}

In Europe, each member state authorises the preparation of compounded preparations for the treatment of patients for whom there is no suitable approved alternative available in the market. Since 2011, member states have been recommended to standardise themselves using the Council of Europe Resolution²⁴ on quality and safety standards for handling to avoid the risks associated with preparation practices²⁵; however there is still large regulatory variability in this regard in Europe.²⁶

Special combinations are usually used in dermatology or oncology treatments but as in the presented cases, combinations could be prepared as cocktails of active substances prescribed for weight loss.

For these combinations, due to the multiple active substances included, there is an increased risk of drug interactions and adverse effects.

Case presentation

Case 1

A 48-year-old woman was admitted due to progressive worsening of pressure-type holocranial headache over 5 days, increasing in supine position and with Valsalva manoeuvres, associated with nausea and resistant to analgesics. Additionally, the patient reported difficulty to keep attention and blurring of vision.

The patient was overweight (body mass index 28.9) had history of ventricular arrhythmia, treated with flecainide 100 mg once a day, and had had a bilateral saphenectomy due to chronic venous insufficiency and phlebothrombosis.

She had started a weight loss compounded preparation 8 months before, composed by: chlordiazepoxide 10 mg, bupropion 100 mg, topiramate 10 mg, metformin 200 mg, furosemide 40 mg, orlistat 50 mg, Cascara sagrada 40 mg, senna glycosides 20 mg, phenolphthalein 80 mg, chromium picolinate 200 mcg and Centella asiatica 200 mg, with the posology of two capsules per day. Oral contraceptive (ethinylestradiol 0.030 mg + gestodene 0.075 mg) was reintroduced 5 months before. She had a history of previous exposure to long-term oral contraceptives, without history of ADRs.

Neurological examination disclosed bradypsychia, disorientation and preservation of speech.

Urgent brain CT and venous CT revealed a CVT of the torcula, bilateral transversal sinus, straight sinus, internal cerebral veins with associated left thalamo-capsular venous infarct (figure 1).

Figure 1.

(A) MRI venography—filling defect of the torcular herophili, proximal lateral sinus and deep venous system confirming cerebral venous thrombosis. (B) Brain MRI—axial T2—bilateral thalamic hyperintensities and oedema.

Laboratory evaluation was normal. Anticoagulation with enoxaparin was started and the patient was admitted to the stroke unit. During the hospitalisation she progressively improved her symptoms and she did not present with any complication. Due to clinical stability, enoxaparin was replaced with warfarin (with enoxaparin bridging) on the seventh day of admission. She was discharged 9 days later, asymptomatic, anticoagulated with warfarin (international normalized ratio 2–3) for 6 months and with indication to stop the oral contraceptive and the weight loss compounded preparation.

Case 2

A 51-year-old woman was admitted for progressive worsening of pressure-type holocranial headache over 2 weeks, exacerbated by physical exercise and Valsalva manoeuvres and resistant to analgesic medication.

She had history of hypothyroidism, treated with levothyroxine 0.1 mg id.

The patient had been taking oral contraceptive (ethinylestradiol 0.030 mg + gestodene 0.075 mg) for over 16 years, with no previous history of ADR, and the year before she had started a compounded preparation prescribed for weight loss composed by: chlordiazepoxide 10 mg, bupropion 120 mg, topiramate 35 mg, metformin 230 mg, furosemide 30 mg, Hoodia gordonii 70 mg, C. sagrada 60 mg and orange extract 200 mg at the dosage of 2 capsules per day.

Neurological examination was normal. CT revealed hyperdensity of the upper longitudinal sinus and torcula and brain MRI confirmed CVT of the superior longitudinal sinus, left lateral sinus, left jugular vein and cortical veins (figure 2). Laboratory evaluation was normal. The patient was admitted to the stroke unit and anticoagulation with enoxaparin was started. During the admission acetazolamide was started due to persistent complaints of headache. She did not present any other complications during admission. Due to clinical stability, enoxaparin was replaced with warfarin (with enoxaparin bridging) on the fifth day of admission. The patient was discharged 6 days later, asymptomatic, anticoagulated with warfarin (international normalized ratio 2–3) for 6 months and with an indication to stop the oral contraceptive and the weight loss compounded preparation.

Figure 2.

(A) Brain CT—spontaneous hyperdensity of the sagittal sinus. (B) Brain MRI coronal T1—hyperintensity of the left lateral sinus confirming acute cerebral venous thrombosis. (C) MRI venography—filling defect of the sagittal sinus, left lateral sinus and left jugular vein.

Outcome and follow-up

The patients were observed in outpatient clinic without recurrence of thrombotic events. Additional testing including thrombophilia and autoimmunity was negative. One year later they are clinically recovered without any other episode of venous thrombosis.

The suspected ADRs were notified to the Regional Pharmacovigilance Centre (Unidade de Farmacovigilância de Lisboa) and causality was assessed with global introspection method as ‘Possible’.

A possible alert signal was raised at Portuguese National Authority of Medicines and Health Products, Infarmed I.P. and is currently being assessed.

Discussion

We report two spontaneous notifications received by the Pharmacovigilance Unit of Lisbon concerning two cases of women who presented CVT, admitted to same stroke unit, during a short period, who raised attention of the possible existing increased risk of CVT in women treated with compounded preparations prescribed for weight loss in association with oral contraceptive.

An additional case report was retrieved from the Portuguese Pharmacovigilance System Database concerning a 47-year-old woman, who presented with ‘cerebral venous infarction’ after oral administration of a compounded preparation for weight loss, composed of: ‘butylpropiophenone’ 100 mg, Cynara cardunculus 300 mg, C. sagrada 60 mg, C. asiatica 400 mg, chlordiazepoxide 5 mg, furosemide 20 mg, H. gordonii 800 mg, and ‘Glimellume’ 300 mg. In this case, no additional risk factor for CVT was present, and concomitant exposure to oral contraceptive or hormone replacement therapy was excluded.^{27 28}

To our knowledge no previous similar cases have been published in the literature, and we believe that it is important to raise the attention on this possible severe adverse reaction, especially when this type of compounded medicines are coadministered with oral contraceptives or whenever any other possible venous thrombosis risk factor is present.

In both the presented cases, no other risk factor for CVT was found, except concomitant medication with oral contraceptive, that in one of the cases had been recently reintroduced. Both patients had no family history of thrombotic disorders, personal history of malignancy, infections, spontaneous miscarriages, deep venous thrombosis, smoking or toxic habits.

In the two cases there is suspicion of additive/synergic interaction of the weight loss compounded preparation in combination with oral contraceptive, increasing the risk of VTE associated with the latter, possibly due to dehydration caused by the diuretics and laxatives contained in the preparations. In one of the patient’s laboratory results at the time of admission did not support dehydration, and dehydration was not specifically studied in the other two.

We would like to emphasise the fact that in the recent past CVT was rarely diagnosed, most likely because milder cases were undetected and incidence estimates were extrapolated from autopsy data therefore determining only fatal cases.

In fact, as pointed out in a recent editorial,²⁹ epidemiology of CVT is changing, probably not because of real difference in incidence but because of improvement of CVT diagnosis: older studies reported lower incidences with more severe presentation and worse outcomes, but after implementation of new imaging tools, the reported incidences have been increasing steadily over time. For this reason, detection of CVT as an ADR could have been more challenging in the past, due to the lower availability of imaging tools and therefore likely under-reported.

No exact recent pharmacoepidemiology data is available about utilisation of this kind of products in the form of compounded preparations, but due to obesity epidemic and to the popularity of both prescription and nonprescription weight loss products,³⁰ it is likely to be a public health concern, which historically started in the USA and more recently became widespread in Spain (famous as fórmulas magistrales para la obesidad) and Brazil.^{31 32}

Antiobesity and anorexigenic drugs have been included in lists of forbidden substances to be used for compounded preparations in several countries, in order to avoid their misuse by means of pharmaceutical compounding; however, strategies to circumvent the law and escape prohibitions are being used, in addition to replacement with non-prescription weight loss products/dietary supplements or the explicitly illegal sale on the internet.³¹

The two compounded preparations of these cases were legally prescribed and dispensed, as Magistral Formula, respecting the current Portuguese law^33–35: no forbidden substances were included and all doses were below the doses contained in licensed product, nevertheless the concept of rational prescription is arguable.

Epidemiologic studies are needed to confirm the association of these products with the suspected adverse reaction of CVT as well as additional investigation to determine the exact underlying mechanisms.

Learning points.

• Raise attention to cerebral venous thrombosis as possible adverse drug reaction to weight loss compounded preparations especially in women taking oral contraceptives.

• Antiobesity and anorexigenic drugs have been included in lists of forbidden substances to be used for compounded preparations in several countries, in order to avoid their misuse; however, strategies to circumvent the law and escape prohibitions are being used.

• No exact recent pharmacoepidemiology data are available about utilisation of compounded preparations for weight loss, but due to the popularity of weight loss products in general, it is likely to be a public health concern.