Adverse effects
Primidone can cause drowsiness, listlessness, ataxia, visual disturbances, nystagmus, headache, and dizziness.[14] These side effects are the most common, reportedly occurring in more than 1% of users.[23] Transient nausea and vomiting are also common side effects.[24]
Dupuytren's contracture, a disease of the fasciae in the palm and fingers that permanently bends the fingers (usually the little and ring fingers) toward the palm, was first noted to be highly prevalent in epileptic people in 1941 by a Dr. Lund, 14 years before primidone was on the market. Lund also noted that it was equally prevalent in individuals with idiopathic and symptomatic epilepsy and that the severity of the epilepsy did not matter. Only one-quarter of the women were affected, though, vs. half of the men.[25] Critcheley et al., 35 years later, reported a correlation between how long a patient had had epilepsy and his or her chance of getting Dupuytren's contracture. They suspected that this was due to phenobarbital therapy, and that the phenobarbital was stimulating peripheral tissue growth factors.[26] Dupuytren's contracture is almost exclusively found in Caucasians, especially those of Viking descent, and highest rates are reported in northern Scotland, Norway, Iceland, and Australia. It has also been associated with alcoholism, heavy smoking, diabetes mellitus, physical trauma (either penetrating in nature or due to manual labor), tuberculosis, and HIV. People with rheumatoid arthritis are less likely to get this, and Drs. Hart and Hooper speculate that this is also true of gout due to the use of allopurinol. This is the only susceptibility factor that is generally agreed upon. Anticonvulsants do not seem to increase the incidence of Dupuytren's contracture in people of color.[25]
Primidone has other cardiovascular effects in beyond shortening the QT interval. Both phenobarbital and it are associated with elevated serum levels (both fasting and six hours after methionine loading) of homocysteine, an amino acid derived from methionine. This is almost certainly related to the low folate levels reported in primidone users. Elevated levels of homocysteine have been linked to coronary heart disease. In 1985, both drugs were also reported to increase serum levels of high-density lipoprotein cholesterol, total cholesterol, and apolipoproteins A and B.[27]
It was first reported to exacerbate hepatic porphyria in 1975. In 1981, phenobarbital, one of primidone's metabolites, was shown to only induced a significant porphyrin level at high concentrations in vitro.[28] It can also cause elevations in hepatic enzymes such as gamma-glutamyl transferase and alkaline phosphatase.[23]
Less than 1% of primidone users experience a rash. Compared to carbamazepine, lamotrigine, and phenytoin, this is very low. The rate is comparable to that of felbamate, vigabatrin, and topiramate.[29] Primidone also causes exfoliative dermatitis, Stevens–Johnson syndrome, and toxic epidermal necrolysis.[23]
Primidone, along with phenytoin and phenobarbital, is one of the anticonvulsants most heavily associated with bone diseases such as osteoporosis, osteopenia (which can precede osteoporosis), osteomalacia, and fractures.[30][31][32] The populations usually said to be most at risk are institutionalized people, postmenopausal women, older men, people taking more than one anticonvulsant, and children, who are also at risk of rickets.[30] Bone demineralization is suggested to be most pronounced in young people (25–44 years of age),[31] and one 1987 study of institutionalized people found that the rate of osteomalacia in the ones taking anticonvulsants—one out of 19 individuals taking an anticonvulsant (vs. none among the 37 people taking none) —was similar to that expected in elderly people. The authors speculated that this was due to improvements in diet, sun exposure, and exercise in response to earlier findings, and/or that this was because it was sunnier in London than in the Northern European countries, which had earlier reported this effect.[32]
Anticonvulsants affect the bones in many ways. They cause hypophosphatemia, hypocalcemia, low vitamin D levels, and increased parathyroid hormone. Anticonvulsants also contribute to the increased rate of fractures by causing somnolence, ataxia, and tremor, which would cause gait disturbance, further increasing the risk of fractures on top of the increase due to seizures and the restrictions on activity placed on epileptic people. Increased fracture rate has also been reported for carbamazepine, valproate, and clonazepam. The risk of fractures is higher for people taking enzyme-inducing anticonvulsants than for people taking enzyme-non-inducing anticonvulsants.[31] In addition to all of the above, primidone can cause arthralgia.[23]
Granulocytopenia, agranulocytosis, red-cell hypoplasia and aplasia, and megaloblastic anemia are rarely associated with the use of primidone.[33] Megaloblastic anemia is actually a group of related disorders with different causes that share morphological characteristics—enlarged red blood cells with abnormally high nuclear-cytoplasmic ratios resulting from delayed maturation of nuclei combined with normal maturation of cytoplasm, into abnormal megakaryocytes and sometimes hypersegmented neutrophils; regardless of etiology, all of the megaloblastic anemias involve impaired DNA replication.[34] The anticonvulsant users who get this also tend to eat monotonous diets devoid of fruits and vegetables.[35]
This antagonistic effect is not due to the inhibition of dihydrofolate reductase, the enzyme responsible for the reduction of dihydrofolic acid to tetrahydrofolic acid, but rather to defective folate metabolism.[36]
In addition to increasing the risk of megaloblastic anemia, primidone, like other older anticonvulsants, also increases the risk of neural tube defects,[37] and like other enzyme-inducing anticonvulsants, it increases the likelihood of cardiovascular defects, and cleft lip without cleft palate.[38] Epileptic women are generally advised to take folic acid,[37] but there is conflicting evidence regarding the effectiveness of vitamin supplementation in the prevention of such defects.[38][39]
Additionally, a coagulation defect resembling vitamin K deficiency has been observed in newborns of mothers taking primidone.[37] Because of this, primidone is a Category D medication.[40]
Primidone, like phenobarbital and the benzodiazepines, can also cause sedation in the newborn and also withdrawal within the first few days of life; phenobarbital is the most likely out of all of them to do that.[37]
In May 2005, Dr. M. Lopez-Gomez's team reported an association between the use of primidone and depression in epilepsy patients; this same study reported that inadequate seizure control, post-traumatic epilepsy, and polytherapy were also risk factors. Polytherapy was also associated with poor seizure control. Of all of the risk factors, use of primidone and inadequate seizure control were the greatest, with odds ratios of 4.089 and 3.084, respectively. They had been looking for factors associated with depression in epilepsy patients.[41] Schaffer et al. 1999 reported that one of their treatment failures, a 45-year-old woman taking 50 mg a day along with lithium 600 mg/day, clozapine 12.5 mg/day, trazodone 50 mg/day, and alprazolam 4 mg/day for three and a half months experienced auditory hallucinations that led to discontinuation of primidone.[42] It can also cause hyperactivity in children;[43] this most commonly occurs at low serum levels.[44] There is one case of an individual developing catatonic schizophrenia when her serum concentration of primidone went above normal.[45]
Primidone is one of the anticonvulsants associated with anticonvulsant hypersensitivity syndrome, with the others being carbamazepine, phenytoin, and phenobarbital. This syndrome consists of fever, rash, peripheral leukocytosis, lymphadenopathy, and occasionally hepatic necrosis.[46]
Hyperammonemic encephalopathy was reported by Katano Hiroyuki of the Nagoya City Higashi General Hospital in early 2002 in a patient who had been stable on primidone monotherapy for five years before undergoing surgery for astrocytoma, a type of brain tumor. Additionally, her phenobarbital levels were inexplicably elevated after surgery. This is much more common with the valproates than with any of the barbiturates.[47] A randomized, controlled trial w found that primidone was more likely to cause impotence than phenytoin, carbamazepine, or phenobarbital.[24] Like phenytoin, primidone is rarely associated with lymphadenopathy.[48] Primidone can also cause vomiting; this happens in 1.0–0.1% of users.[23]
Overdose
The most common symptoms of primidone overdose are coma with loss of deep tendon reflexes, and during the recovery period, if the patient survives, disorientation, dysarthria, nystagmus, and ataxia,[49] lethargy, somnolence, vomiting, nausea, and occasionally, focal neurological deficits which lessen over time.[50] Complete recovery comes within five to seven days of ingestion.[49] The symptoms of primidone poisoning have generally been attributed to its biotransformation to phenobarbital, but primidone has toxic effects independent of its metabolites in humans.[50] The massive crystalluria that sometimes occurs sets its symptom profile apart from that of phenobarbital.[49][51]
