Objective: It is very difficult to identify the frequency of rare adverse drug reactions (ADRs) precisely.  A study was conducted to estimate the frequency of ADRs that were not observed in clinical studies by referring to the sales volume of the pharmaceuticals until the date when the ADR was first observed after a drug was marketed.
Methods and Subjects: The study was conducted for the 17 pharmaceuticals to estimate the frequency of Hepatopathy.  The date of report of the ADR to the Minister was obtained through information disclosure requests.  The sales volume of the relevant pharmaceuticals was provided by IMS Japan.  On the premise that all the ADRs were detectable, the probability (P) that an ADR was not detected right before drug administration in the first case of the ADR was estimated through Formula 1.
Formula 1 : P=1−{(D₀−S)!÷(D₀−S−D_N)!}/{D₀!÷(D₀−D_N)!} = 1−{(D₀−D₀×F)!÷(D₀−D₀×F−D_N)!}/{D₀!÷(D₀−D_N)!}
  D₀ referred to the estimated person-days for all the patients subject to the drug therapy, S to the number of patients with ADR, D_N to the person-days until the date when the ADR was observed and F to the frequency of the ADR.  F was estimated where the detection P was 0.95 or was close to 0.95.
Results and Discussion: Among the pharmaceuticals investigated, the frequency was highest in product A (0.038%) and was lowest in product X (0.0000088%).  In many cases, the package inserts describe the frequencies of rare ADRs as unknown.  However, the frequency can be estimated relatively precisely through the method stated above using data, which may be kept by pharmaceutical manufacturers.

Reversible cerebral vasoconstriction syndrome (RCVS) presents with characteristic clinical, brain imaging, and angiographic findings. The most common clinical feature of RCVS is a severe acute headache, which is often referred to as a thunderclap headache owing to the nature of its presentation. It may occur spontaneously or may be provoked by various precipitating factors. We present two cases of RCVS concomitant with cerebral venous sinus thrombosis (CVST). Patient 1 was a 42-yearold woman admitted to our hospital with severe headache radiating to the neck, with associated vomitting. She had a history of ovarian cancer and underwent an operation for resection of the tumor a month prior to presentation. After resection, her estradiol (E2) levels were reduced from 288 pg/ ml to 31 pg/ml (normal range, 0-49 pg/ml). Initial imaging upon admission to our hospital revealed left posterior convexity subarachnoid hemorrhage. Magnetic resonance angiography (MRA) showed findings consistent with RCVS affecting the left posterior cerebral artery. Magnetic resonance venography (MRV) showed CVST of the left transverse and sigmoid sinuses. Single photon emission computed tomography (SPECT) showed a left posterior ischemic lesion. These findings improved following treatment with nimodipine and anticoagulant. Patient 2 was a 39-year-old woman presented with holocranial headache associated with vomiting. She was diagnosed with an ovarian tumor. She underwent an operation three months prior to presentation. After tumor resection, her E2 level decrease from 193 pg/ml to 19 pg/ml (normal range, 0-49 pg/ml). MRA confirmed the presence of a vasospasm involving the right anterior cerebral artery. MRV confirmed the presence of thrombosis involving the superior sagittal sinus. She was discharged on postpartum day 31 without neurological deficits after treatment with anticoagulants. At 3 month follow-up, both MRA and MRV were within the normal limits. In conclusion, this is the first report of two women diagnosed with RCVS with concomitant CVST following ovarian tumor resection. The rapid change of perioperative E2 levels may have contributed to the development of CVST and RCVS.