Undesirable effects in patients receiving Ranexa are generally mild to moderate in severity and often develop within the first 2 weeks of treatment. These were reported during the Phase 3 clinical development programme, which included a total of 1,030 chronic angina patients treated with Ranexa.
The adverse events, considered to be at least possibly related to treatment, are listed below by body system, organ class, and absolute frequency. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and very rare (< 1/10,000).
Metabolism and nutrition disorders:
Uncommon: anorexia, decreased appetite, dehydration. Rare: hyponatremia.
Uncommon: anxiety, insomnia, confusional state, hallucination. Rare: disorientation.
Nervous system disorders:
Common: dizziness, headache. Uncommon: lethargy, syncope, hypoaesthesia, somnolence, tremor, postural dizziness, paresthesia. Rare: amnesia, depressed level of consciousness, loss of consciousness, coordination abnormal, gait disturbance, parosmia.
Uncommon: blurred vision, visual disturbance, diplopia.
Ear and labyrinth disorders:
Uncommon: vertigo, tinnitus. Rare: impaired hearing.
Uncommon: hot flush, hypotension. Rare: peripheral coldness, orthostatic hypotension.
Respiratory, thoracic, and mediastinal disorders:
Uncommon: dyspnoea, cough, epistaxis. Rare: throat tightness.
Common: constipation, vomiting, nausea. Uncommon: abdominal pain, dry mouth, dyspepsia, flatulence, stomach discomfort. Rare: pancreatitis, erosive duodenitis, oral hypoaesthesia.
Skin and subcutaneous tissue disorders:
Uncommon: pruritus, hyperhydrosis. Rare: angioedema, allergic dermatitis, urticaria, cold sweat, rash.
Musculoskeletal and connective tissue disorders:
Uncommon: pain in extremity, muscle cramp, joint swelling, muscular weakness.
Renal and urinary disorders:
Uncommon: dysuria, haematuria, chromaturia. Rare: acute renal failure, urinary retention.
Reproductive system and breast disorders:
Rare: erectile dysfunction.
General disorders and administration site conditions:
Common: asthenia. Uncommon: fatigue, peripheral oedema.
Uncommon: increased blood creatinine, increased blood urea, prolonged QT corrected interval, increased platelet or white blood cell count, decreased weight. Rare: elevated levels of hepatic enzyme.
The adverse event profile was generally similar in the MERLIN-TIMI 36 study. In this long term study, acute renal failure was also reported with an incidence less than 1% in placebo and ranolazine patients. Evaluations in patients who may be considered at higher risk of adverse events when treated with other antianginal medicinal products, e.g. patients with diabetes, Class I and II heart failure, or obstructive airway disease, confirmed that these conditions were not associated with clinically meaningful increases in the incidence of adverse events. An increased incidence of adverse events was seen among ranolazine treated patients in the RIVER-PCI trial (see Pharmacology: Pharmacodynamics under Actions) where patients with incomplete revascularization post-PCI were given ranolazine up to 1000 mg twice daily or placebo for approximately 70 weeks. In this study, there was a higher reporting rate for congestive heart failure in the ranolazine group (2.2% vs 1.0% in placebo). Also, transient ischemic attack occurred more frequently in patients treated with ranolazine 1000 mg twice daily compared with placebo (1.0% vs 0.2%, respectively); however, the incidence of stroke was similar between treatment groups (ranolazine 1.7% vs placebo 1.5%).
Elderly, renal impairment, and low weight:
In general, adverse events occurred more frequently among elderly patients and patients with renal impairment; however, the types of events in these subgroups were similar to those observed in the general population. Of the most commonly reported, the following events occurred more often with Ranexa (placebo-corrected frequencies) in elderly (≥ 75 years of age) than younger patients (< 75 years of age): constipation (8% versus 5%), nausea (6% versus 3%), hypotension (5% versus 1%), and vomiting (4% versus 1%).
In patients with mild or moderate renal impairment (creatinine clearance ≥ 30-80 ml/min) compared to those with normal renal function (creatinine clearance > 80 ml/min), the most commonly reported events and their placebo-corrected frequencies included: constipation (8% versus 4%), dizziness (7% versus 5%), and nausea (4% versus 2%).
In general, the type and frequency of adverse events reported in patients with low body weight (≤ 60 kg) were similar to those of patients with higher weight (> 60 kg); however, the placebo-corrected frequencies of the following common adverse events were higher in low body weight than heavier patients: nausea (14% versus 2%), vomiting (6% versus 1%), and hypotension (4% versus 2%).
Small, clinically insignificant, reversible elevations in serum creatinine levels have been observed in healthy subjects and patients treated with Ranexa. There was no renal toxicity related to these findings. A renal function study in healthy volunteers demonstrated a reduction in creatinine clearance with no change in glomerular filtration rate consistent with inhibition of renal tubular secretion of creatinine.