A case report on nimesulide and its relation with angina

Salman, M. T.; Rahman, S. Z. and Khan, R. A. (2003) A case report on nimesulide and its relation with angina. In: International Workshop on Adverse Drug-Reaction Monitoring & 3rd Annual Conference Society of Pharmacovigilance, India, 11-13 Dec 2003, Agra, India.

Even though there might be several cases of NSAIDs induced angina that are not been reported, we could find a definite case of Nimesulide induced angina in Aligarh. A 65 year old female patient was a known case of diabetes mellitis for 17 years and angina pectoris for 10 years for which she was maintained on drugs. She sustained injury after falling down and was found to have Colle’s fracture for which she was advised POP and Tab Nimesulide twice daily alongwith ongoing treatment. On 3rd day, she felt chest pain (angina) for which she used Tab sorbitrate 3-4 times a day but no improvement was noticed. Then she consulted her family physician. On examination, no abnormality was found except that ECG showed changes of ischemia and extra systoles. She was diagnosed as a case of Unstable Angina and advised to stop the suspected drug Nimesulide but continue to take previous treatment. She then showed improvement in angina. As an alternative Tab Brufen (Ibuprofen) 400 mg thrice daily was advised. The patient afterwards complained no problem. In this case, the unstable angina appears to be due to coronary spasm and not due to clot because on withdrawing the suspected drug there was rapid relief. The spasm seems to be related to inherent properties of Nimesulide and not due to prostaglandin inhibition as Brufen did not cause the same symptoms. Alternatively, it may be due to an imbalance between COX 1 and COX 2 activities due to preferencial COX 2 inhibition. Moreover, the inhibition of prostaglandin synthesis may adversely affect cardiovascular homeostasis.

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Serious hepatic reactions associated with the dietary supplement Fortodol

Herb-based dietary supplement contained active drug substance.

> The Medical Products Agency issues a warning against the herb-based dietary supplement Fortodol. The product has been on sale in Sweden since 2004. Analyses of the product revealed that it contains the drug substance nimesulide which is suspected to have caused serious liver injuries including liver failure and cardiovascular events with fatal outcome. At least 240 000 jars totalling 24 million capsules is reported having been sold in Sweden and Norway since 2004.

> The Medical Products Agency has received information about four cases of liver damage among Swedish patients who have taken Fortodol. In one of the cases, this led to acute liver failure resulting in death of the patient. The Norwegian Medical Products Agency has information about five cases of liver damage, and one case of death, with temporal association with the intake of Fortodol. It is known that the substance nimesulide can cause serious liver injury. Nimesulide is not an approved medicinal product in Sweden.

>  People consuming Fortodol should immediately cease the intake of it. Should you suffer from symptoms such as poor appetite, nausea, vomiting, abdominal pain, fatigue, dark urine or yellow skin, you should contact a medical care facility for a liver check up, says Barbro Gerdén, physician at the Medical Products Agency.

> The dietary supplement Fortodol, which is on sale on the Internet and in health food shops is said to relieve arthritis and muscle pains as well as head aches. The table of contents specifies that the product contains turmeric extract and the amino acid dl-phenylalanine. In two of nine analysed batches, the Medical Products Agency found the drug substance nimesulide.

> In those EU-countries where nimesulide is approved as a medicinal product the recommendations state that the substance should only be used for temporary treatments with prescriptions of not more than 30 doses. Fortodol has been sold in packages of up to 100 capsules.

> This is a product which has been launched as a dietary supplement, not as a medicinal product which implies a risk that people use it for longer periods of time, says Per Claeson, pharmacist at the Medical Products Agency.

> This is not the first time that the Medical Products Agency finds hazardous levels of drug substances in products sold as herbal products. Earlier examples are weight loss products and potency enhancers. This is the first time that an illegal drug substance has been discovered in a product used by people with painful disease states such as joint and muscle ailments. 

Case report on Nimesulide induced Angina

New Pharmacological Drug Classes Introduced in 2008

Pharmacologic Class	First to be Marketed in the U.S.	FDA Approved Indication	11th Edition Reference
C1 inhibitor	C1 inhibitor (Cinryze)	Routine prophylaxis against angioedema attacks in patients with hereditary angioedema	page 1405
CXCR4 chemokine receptor inhibitor	plerixa (Mozobil)	Mobilization of granulocyte-colony stimulating factor induced hematopoietic stem cells to the peripheral blood prior to collection	page 1274
peripherally acting µ-opioid receptor antagonist	alvimopan (Entereg)	Acceleration of the time to gastrointestinal recovery following bowel surgery	pages 561-562
	methylnaltrexone (Relistor)	Treatment of opioid-induced constipation
thrombopoietin receptor agonist	eltrombopag (Promacta)	Treatment of thrombocytopenia in patients with chronic immune thrombocytopenic purpura	pages 1441-1442
	romiplostim (Nplate)

Drugs Licensed in 2008 With Mechanisms Similar to Previously Approved Drugs

Generic Name	Brand Name	Pharmacology	2008 FDA Approved Indication	Pharmacologically Similar Agents	11th Edition Reference
bendamustine	Treanda	alkylating agent	Treatment of chronic lymphocytic leukemia	busulfan, carmustine, chlorambucil, cyclophosphamide, ifosfamide, melphalan	pages 1322-1327
certolizumab	Cimzia	tumor necrosis factor inhibitor	Management of Chron's disease	infliximab	page 1419
clevidipine	Cleviprex	dihydropyridine calcium channel antagonist	Treatment of hypertension	amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine nisoldipine	pages 832-838, 857-858
degarelix	none	GnRH receptor antagonist	Treatment of prostate cancer	goserelin, histrelin, leuprolide, triptorelin	pages 1387-1388
desvenlafaxine (major metabolite of venlafaxine)	Pristiq	selective serotonin and norepinephrine reuptake inhibitor	Treatment of major depressive disorder	venlafaxine	pages 434t, 437t, 439t, 444t,
difluprednate	Durezol	opthalmic corticosteroid	Treatment of ocular inflammation	prednisolone	pages 1724-1725
ethinyl estradiol/levonorgestrel	LoSeasonique	oral contraceptive	Prevention of pregnancy	ethinyl estradiol/levonorgestrel (Seasonique)	pages 1563-1567
etravirine	Intelence	non-nucleoside reverse transcriptase inhibitor	Treatment of HIV-1 infection	delavridine, efavirenz, nevirapine	pages 1292-1297
fesoterodine	Toviaz	muscarinic receptor antagonist	Treatment of overactive bladder	darifenacin, solifenacin, tolterodine	pages 173-174
fosaprepitant (produrg of aprepitant)	Emend	substance P/neurokinin 1 receptor antagonist	Prevention of nausea and vomiting associated with emetogenic cancer chemotherapy	aprepitant	pages 1005
fospropofol (produrg of propofol)	Lusedra	sedative-hypnotic	Monitored anesthesia care sedation	propofol	pages 350-351
gadofosveset	Vasovist	gadolinium-based contrast agent	Magnetic resonance imaging	gadodiamide, gadoteridol
gadoxetate	Requip XL
regadenoson	Lexiscan	adenosine receptor agonist	Pharmacologic stress agent for radionuclide myocardial perfusion imaging	adenosine	page 917
rilonacept (also known as IL-1 Trap)	Arcalyst	interleukin-1 blocker	Treatment of cryopyrin-associated periodic syndromes, including Familial Cold Autoinflammatory Syndrome and Muckle-Wells Syndrome	anakinra	page 672
silodosin	Rapaflo	alpha-1 adrenergic receptor antagonist	Treatment of benign prostatic hyperplasia	prazosin, terazosin, doxazosin, tamsulosin, alfuzosin	pages 269-271
tapentadol	none	m-opioid receptor agonist & norepinephrine reuptake inhibittor	Relief of pain	tramadol	page 566
tetrabenazine	Xenazine	monoamine depletor	Treatment of chorea associated with Huntington´s disease	reserpine	pages 173, 541

Final Results of ACCOMPLISH Show Benefit of Fixed-Dose Combination as Initial Therapy

The main results of the ACCOMPLISH trial, which demonstrated the superiority of a combination of initiating antihypertensive therapy with an ACE inhibitor plus a calcium channel blocker (CCB) over initiating with a thiazide-type diuretic, have been published in The New England Journal of Medicine, approximately 9 months after preliminary findings were presented at the annual Scientific Sessions of the American College of Cardiology. These results challenge current US hypertension guidelines, which recommend inclusion of a diuretic in first-line combination therapy.

Between 2003 and 2005, the international ACCOMPLISH trial randomized 11,506 patients with hypertension (mean age 68.4 years) who were at high risk for cardiovascular events to receive treatment with either benazepril plus amlodipine or benazepril plus hydrochlorothiazide (HCTZ) as single capsule formulations. The only other antihypertensive medications permitted were beta-blockers, alpha-blockers, clonidine, and spironolactone. The trial was terminated early, after a mean follow-up of 36 months, when an interim analysis showed overwhelming efficacy in favor of the benazepril-amlodipine combination. Mean blood pressures after dose adjustment were 131.6/73.3 mm Hg in the benazepril-amlodipine group and 132.5/74.4 mm Hg in the benazepril-HCTZ group. Rates of blood pressure control (<>

The primary endpoint was the composite of death from cardiovascular causes, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization. There were 552 primary-outcome events in the benazepril-amlodipine group (9.6%) compared with 679 in the benazepril-HCTZ (11.8%), representing an absolute risk reduction with benazepril-amlodipine therapy of 2.2% and a relative risk reduction of 19.6%. For the secondary endpoint of death from cardiovascular causes, nonfatal MI, and nonfatal stroke, the hazard ratio was 0.79. Rates of adverse events were similar in the 2 treatment groups and consistent with those observed from clinical experience with the drugs.

In a press release issued by the University of Michigan Health System, Ann Arbor,  lead investigator Kenneth Jamerson, MD, said, "This robust study showed us that switching patients to a single-pill combination meant that twice as many patients got to their blood pressure goal, regardless of previous therapy. The significant reduction in cardiovascular events we observed in patients will, I hope, show physicians that earlier use of a combination medication, especially with amlodipine, may be in the best interest of patients."

caution against combining the 2 classes of RAS inhibitors

The updated recommendation is based on the results of the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), an international study supported by Boehringer Ingelheim, the Heart and Stroke Foundation of Ontario, and the Canadian Institutes of Health Research. The main results of ONTARGET, published in 2008,^[9] showed that in 25,620 patients with vascular disease or type 2 diabetes, the combination therapy had a greater blood pressure-lowering effect than either telmisartan or ramipril alone, but it did not produce any additional benefit in terms of patient outcomes, and it was associated with more side effects, such as hyperkalemia, hypotension, and renal impairment. The guidelines also note that in patients with stage 3 chronic kidney disease (glomerular filtration rate > 30 mL/min) the ACE inhibitor plus ARB combination reduced urine protein but did not reduce cardiovascular outcomes, and it worsened renal outcomes, including the need for acute dialysis compared with the ACE inhibitor alone.

The only data to support improved patient outcomes with the combination of an ACE inhibitor plus an ARB are in people with heart failure, where, the guidelines note, the combination reduces recurrent hospitalization. Hence, the guidelines advise that the use of combination of ACE inhibitor with an ARB therapy should only be considered in selected and closely monitored people with advanced heart failure or proteinuric nephropathy. They advise that for people already on the combination and stable, physicians should consider that prescribing 1 of the 2 drug classes alone will reduce cardiovascular events to the same extent and that other therapeutic regimens have the potential to reduce cardiovascular events and blood pressure to a greater degree. Trials are ongoing of a combination of an ACE inhibitor with an ARB in people with chronic kidney disease and diabetes.

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