Nifedipine

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Nifedipine
Nifedipine substance photo.jpg
Nifedipine.svg Nifedipine-from-xtal-3D-balls.png
Clinical data
Trade names Adalat, Procardia, others
AHFS/Drugs.com Monograph
MedlinePlus a684028
License data
Pregnancy
category
Routes of
administration 		By mouth, topical
Drug class Calcium channel blocker (dihydropyridine) [2]
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 45-56%
Protein binding 92-98%
Metabolism Gastrointestinal, Liver
Elimination half-life 2 hours
Excretion Kidneys: >50%, bile duct: 5-15%
Identifiers
  • 3,5-dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.040.529 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H18N2O6
Molar mass 346.339 g·mol−1
3D model (JSmol)
Melting point 173 °C (343 °F)
  • O=C(OC)\C1=C(\N/C(=C(/C(=O)OC)C1c2ccccc2[N+]([O-])=O)C)C
  • InChI=1S/C17H18N2O6/c1-9-13(16(20)24-3)15(14(10(2)18-9)17(21)25-4)11-7-5-6-8-12(11)19(22)23/h5-8,15,18H,1-4H3 Yes check.svgY
  • Key:HYIMSNHJOBLJNT-UHFFFAOYSA-N Yes check.svgY
   (verify)

Nifedipine, sold under the brand names Adalat and Procardia among others, is a calcium channel blocker medication used to manage angina, high blood pressure, Raynaud's phenomenon, and premature labor. [2] It is one of the treatments of choice for Prinzmetal angina. [2] It may be used to treat severe high blood pressure in pregnancy. [2] Its use in preterm labor may allow more time for steroids to improve the baby's lung function and provide time for transfer of the mother to a well qualified medical facility before delivery. [2] It is a calcium channel blocker of the dihydropyridine type. [2] Nifedipine is taken by mouth and comes in fast- and slow-release formulations. [2]

Contents

Common side effects include lightheadedness, headache, feeling tired, leg swelling, cough, and shortness of breath. [2] Serious side effects may include low blood pressure and heart failure. [2] Nifedipine is considered safe in pregnancy and breastfeeding. [4]

Nifedipine was patented in 1967, and approved for use in the United States in 1981. [2] [5] [6] It is on the World Health Organization's List of Essential Medicines. [7] It is available as a generic medication. [2] In 2020, it was the 135th most commonly prescribed medication in the United States, with more than 4 million prescriptions. [8] [9]

Medical uses

High blood pressure

The approved uses are for the long-term treatment of hypertension and angina pectoris. In hypertension, recent clinical guidelines generally favour diuretics and ACE inhibitors, although calcium channel antagonists, along with thiazide diuretics, are still favoured as primary treatment for patients over 55 and black patients. [10]

Nifedipine given as sublingual administration has previously been used in hypertensive emergencies. It was once frequently prescribed on an as-needed basis to patients taking MAOIs for real or perceived hypertensive crises. [11] This was found to be dangerous, and has been abandoned. Sublingual administration of nifedipine promotes a hypotensive effect via peripheral vasodilation. It can cause an uncontrollable decrease in blood pressure, reflex tachycardia, and a steal phenomenon in certain vascular beds. There have been multiple reports in the medical literature of serious adverse effects with sublingual nifedipine, including cerebral ischemia/infarction, myocardial infarction, complete heart block, and death. As a result of this, in 1985 the FDA reviewed all data regarding the safety and effectiveness of sublingual nifedipine for the management of hypertensive emergencies, and concluded that the practice should be abandoned because it was neither safe nor effective. [12] [13] An exception to the avoidance of this practice is in the use of nifedipine for the treatment of hypertension associated with autonomic dysreflexia in spinal cord injury. [14]

Early labor

Nifedipine has been used frequently as a tocolytic (agent that delays premature labor). A Cochrane review has concluded that it has benefits over placebo or no treatment for prolongation of pregnancy. It also has benefits over beta-agonists and may also have some benefits over atosiban and magnesium sulfate, although atosiban results in fewer maternal adverse effects. No difference was found in the rate of deaths among babies around the time of birth, while data on longer-term outcomes is lacking. [15]

Other

Raynaud's phenomenon is often treated with nifedipine. A 2005 meta-analysis showed modest benefits (33% decrease in attack severity, 2.8-5 reduction in absolute number of attacks per week); it does conclude that most included studies used low doses of nifedipine. [16]

Topical nifedipine has been shown to be as effective as topical nitrates for anal fissures. [17]

Nifedipine is also used in high-altitude medicine to treat high altitude pulmonary edema. [18]

Nifedipine is one of the main choices for the treatment of Prinzmetal angina due to its vasodilating effects on the coronary arteries. [2]

Other uses include painful spasms of the esophagus such as from cancer or tetanus.[ medical citation needed ] It is also used for the small subset of people with pulmonary hypertension.[ medical citation needed ]

Finally, nifedipine can be used in the treatment of renal calculi, which are commonly referred to as kidney stones. Studies have indicated that it helps to relieve renal colic. However, alpha blockers (such as tamsulosin) have been described as being significantly better. [19]

Side effects

Nifedipine rapidly lowers blood pressure, and patients are commonly warned they may feel dizzy or faint after taking the first few doses. Tachycardia (fast heart rate) may occur as a reaction. These problems are much less frequent in the sustained-release preparations of nifedipine.[ medical citation needed ]

Extended release formulations of nifedipine should be taken on an empty stomach, and patients are warned not to consume anything containing grapefruit or grapefruit juice, as they raise blood nifedipine levels. There are several possible mechanisms, including the inhibition of CYP3A4-mediated metabolism. [20]

As calcium channel blocker, nifedipine has a risk of causing gingival hyperplasia. [21]

Overdose

A number of persons have developed toxicity due to acute overdosage with nifedipine, either accidentally or intentionally, and via either oral or parenteral administration. The adverse effects include lethargy, bradycardia, marked hypotension and loss of consciousness. The drug may be quantified in blood or plasma to confirm a diagnosis of poisoning, or to assist in a medicolegal investigation following death. Analytical methods usually involve gas or liquid chromatography and specimen concentrations are usually in the 100-1000 μg/L range. [22] [23]

Mechanism of action

Nifedipine is a calcium channel blocker. Although nifedipine and other dihydropyridines are commonly regarded as specific to the L-type calcium channel, they also possess nonspecific activity towards other voltage-dependent calcium channels. [24] [25]

Nifedipine has additionally been found to act as an antagonist of the mineralocorticoid receptor, or as an antimineralocorticoid. [26]

History

Nifedipine (initially BAY a1040, then Adalat) was developed by the German pharmaceutical company Bayer, with most initial studies being performed in the early 1970s. [27]

Official document Otto-Bayer prize, 1991 Urkunde Otto-Bayer-Medaille fur galenische Erfindung Coprazipitat.jpg
Official document Otto-Bayer prize, 1991
Letter Dr Knut Schauerte, patent rights Adalat tablets, 1987. Source: Family archive. Letter Dr Knut Schauerte, patent rights Adalat, 1987.pdf
Letter Dr Knut Schauerte, patent rights Adalat tablets, 1987. Source: Family archive.

Adalat was the first German pharmaceutical to be awarded the prestigious Prix Galien in 1980. [28] In the same year, Ahmed Hegazy submitted his invention (in collaboration with Klaus-Dieter Rämsch) of an extended release, solid medicinal preparation of nifedipine to the German Patent Office in Munich, patenting the "use of nifedipine crystals with a specific surface area of 1-4 m2/g for the production of solid medicinal formulations for achieving long-lasting blood levels for the oral treatment of hypertension by administration 1 to 2 times", [29] an invention that became known as Adalat retard from Bayer (see letter Dr Schauerte). [29] In that formulation, the active ingredient is released over a period of up to 36 hours. [30] With the increasing incidence of heart disease in that period—heart failure became the first cause of death in West Germany [31] —and the new formulation, the medication replaced Aspirin in the 1990s as the biggest single product of Bayer. [32] As Alexander Mey noted, "[d]iese Maßnahmen führten dazu, dass der Umsatz im Jahr 2000 auf 1,7 Mrd. US-$ stieg, obwohl das Präparat bereits ein Vierteljahrhundert am Markt war." [33] On 14 October 1991, Hegazy was awarded the Otto Bayer Medal—no relation to the company founder—for his work solubilizing poorly soluble active ingredients such as nifedipine, a prize, that the Bayer Group has been using to honor excellent research since 1984. By 2020, 528 researchers had received the award. [34] A 1995 US lawsuit, in which Hegazy defended his patent, found that Pfizer's Procardia XL product was also based on his European patent No. 0047899, United States Patent 5264446. [35]

The use of nifedipine and related calcium channel antagonists was much reduced in response to 1995 trials that mortality was increased in patients with coronary artery disease who took nifedipine. [36] This study was a meta-analysis, and demonstrated harm mainly in short-acting forms of nifedipine (that could cause large fluctuations in blood pressure) and at high doses of 80 mg a day and more. [37]

Society and culture

Brand names

In India, nifedipine is manufactured by JB Chemicals, and comes in brands Nicardia Retard (Nifedipine 10 mg, 20 mg tablets) and Nicardia XL 30/60, which are Nifedipine Extended Release tablets. [38]

In Switzerland, nifedipine is sold only as a generic version of extended release formulation, under the names Nifedipin Mepha and Nifedipin Spirig. [39]

Related Research Articles

An antianginal is a drug used in the treatment of angina pectoris, a symptom of ischaemic heart disease.

Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as medications to decrease blood pressure in patients with hypertension. CCBs are particularly effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients. Calcium channel blockers are also frequently used to alter heart rate, to prevent peripheral and cerebral vasospasm, and to reduce chest pain caused by angina pectoris.

Antihypertensives are a class of drugs that are used to treat hypertension. Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infarction. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34% and of ischaemic heart disease by 21%, and can reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. There are many classes of antihypertensives, which lower blood pressure by different means. Among the most important and most widely used medications are thiazide diuretics, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists (ARBs), and beta blockers.

<span class="mw-page-title-main">Amlodipine</span> Medication against high blood pressure

Amlodipine, sold under the brand name Norvasc among others, is a calcium channel blocker medication used to treat high blood pressure, coronary artery disease (CAD) and variant angina. It is taken orally.

<span class="mw-page-title-main">Diltiazem</span> Calcium channel blocker medication

Diltiazem, sold under the brand name Cardizem among others, is a nondihydropyridine calcium channel blocker medication used to treat high blood pressure, angina, and certain heart arrhythmias. It may also be used in hyperthyroidism if beta blockers cannot be used. It is taken by mouth or injection into a vein. When given by injection, effects typically begin within a few minutes and last a few hours.

<span class="mw-page-title-main">Indapamide</span> Thiazide diuretic drug

Indapamide is a thiazide-like diuretic drug used in the treatment of hypertension, as well as decompensated heart failure. Combination preparations with perindopril are available. The thiazide-like diuretics reduce risk of major cardiovascular events and heart failure in hypertensive patients compared with hydrochlorothiazide with a comparable incidence of adverse events. Both thiazide diuretics and thiazide-like diuretics are effective in reducing risk of stroke. Both drug classes appear to have comparable rates of adverse effects as other antihypertensives such as angiotensin II receptor blockers and dihydropyridine calcium channel blockers and lesser prevalence of side-effects when compared to ACE-inhibitors and non-dihydropyridine calcium channel blockers.

<span class="mw-page-title-main">Isosorbide mononitrate</span> Chemical compound

Isosorbide mononitrate, sold under many brand names, is a medication used for heart-related chest pain (angina), heart failure and esophageal spasms. It can be used both to treat and to prevent heart-related chest pain; however, it is generally less preferred than beta blockers or calcium channel blockers. It is taken by mouth.

<span class="mw-page-title-main">Felodipine</span> Medication of the calcium channel blocker type

Felodipine is a medication of the calcium channel blocker type that is used to treat high blood pressure.

<span class="mw-page-title-main">Nimodipine</span> Antihypertensive drug of the calcium channel blocker class

Nimodipine, sold under the brand name Nimotop among others, is calcium channel blocker used in preventing vasospasm secondary to subarachnoid hemorrhage. It was originally developed within the calcium channel blocker class as it was used for the treatment of high blood pressure, but is not used for this indication.

<span class="mw-page-title-main">Nicardipine</span> Antihypertensive drug of the calcium channel blocker class

Nicardipine (Cardene) is a medication used to treat high blood pressure and angina. It belongs to the dihydropyridine class of calcium channel blockers (CCBs). It is also used for Raynaud's phenomenon. It is available in by mouth and intravenous formulations. It has been used in percutaneous coronary intervention.

<span class="mw-page-title-main">Nebivolol</span> Chemical compound

Nebivolol is a beta blocker used to treat high blood pressure and heart failure. As with other β-blockers, it is generally a less preferred treatment for high blood pressure. It may be used by itself or with other blood pressure medication. It is taken by mouth.

Hypertensive encephalopathy (HE) is general brain dysfunction due to significantly high blood pressure. Symptoms may include headache, vomiting, trouble with balance, and confusion. Onset is generally sudden. Complications can include seizures, posterior reversible encephalopathy syndrome, and bleeding in the back of the eye.

<span class="mw-page-title-main">Lercanidipine</span> Antihypertensive drug of the calcium channel blocker class

Lercanidipine is an antihypertensive drug. It belongs to the dihydropyridine class of calcium channel blockers, which work by relaxing and opening the blood vessels allowing the blood to circulate more freely around the body. This lowers the blood pressure and allows the heart to work more efficiently.

<span class="mw-page-title-main">Isradipine</span> Antihypertensive drug of the calcium channel blocker class

Isradipine is a calcium channel blocker of the dihydropyridine class. It is usually prescribed for the treatment of high blood pressure in order to reduce the risk of stroke and heart attack.

<span class="mw-page-title-main">Nisoldipine</span> Antihypertensive drug of the calcium channel blocker class

Nisoldipine is a pharmaceutical drug used for the treatment of chronic angina pectoris and hypertension. It is a calcium channel blocker of the dihydropyridine class. It is sold in the United States under the proprietary name Sular. Nisoldipine has tropism for cardiac blood vessels.

<span class="mw-page-title-main">Manidipine</span> Antihypertensive drug of the calcium channel blocker class

Manidipine is a calcium channel blocker that is used clinically as an antihypertensive.

<span class="mw-page-title-main">Cilnidipine</span> Antihypertensive drug of the calcium channel blocker class

Cilnidipine is a calcium channel blocker. Cilnidipine is approved for use in Japan, China, India, Nepal, and Korea for hypertension.

<span class="mw-page-title-main">Efonidipine</span> Antihypertensive drug of the calcium channel blocker class

Efonidipine (INN) is a dihydropyridine calcium channel blocker marketed by Shionogi & Co. of Japan. It was launched in 1995, under the brand name Landel (ランデル). The drug blocks both T-type and L-type calcium channels. Drug Controller General of India (DCGI) has approved the use of efonidipine in India. It is launched under the brand name "Efnocar".

<span class="mw-page-title-main">Levamlodipine</span> Chemical compound

Levamlodipine (INN), also known as levoamlodipine or S-amlodipine is a pharmacologically active enantiomer of amlodipine. Amlodipine belongs to the dihydropyridine group of calcium channel blocker used as an antihypertensive and antianginal agent. It was approved by the U.S. FDA in December 2019 and is currently marketed under the brand name Conjupri.

<span class="mw-page-title-main">Ahmed Hegazy (pharmacist)</span> Egyptian-German pharmacist (1939–2021)

Ahmed Hegazy was an Egyptian-German pharmacist. He conducted research in the Pharmaceutical Technology Department of Bayer from 1966 to 1999, during which time he invented a new galenic formulation for the active components nifedipine and nimodipine. By blocking calcium channels, the substance has a relaxing effect on vascular muscles and is therefore used for the treatment of hypertension. In 1991, Hegazy received the Otto Bayer Medal for the solubilization of poorly soluble ingredients such as nimodipine. His galenic invention is still the basis for many modern formulations at Bayer AG.

References

  1. ↑ "Nifedipine Pregnancy and Breastfeeding Warnings". Archived from the original on 21 December 2015. Retrieved 25 December 2015.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 "Nifedipine". The American Society of Health-System Pharmacists. Archived from the original on 8 August 2018. Retrieved 17 September 2019.
  3. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  4. ↑ "Nifedipine". Drugs and Lactation Database. Bethesda (MD): National Institute of Child Health and Human Development. 15 August 2023. PMID   30000106 . Retrieved 14 October 2023.
  5. ↑ Sliskovic DR (2013). "Cardiovascular Drugs". In Li JJ, Corey EJ (eds.). Drug Discovery: Practices, Processes, and Perspectives. Hoboken, NJ: John Wiley & Sons. pp. 141–204. ISBN   9781118354469. Archived from the original on 1 September 2017. Retrieved 20 January 2022. p. 172: nifedipine...1,4-dihydropyrine originally approved in 1981.
  6. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 464. ISBN   9783527607495.
  7. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  8. ↑ "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  9. ↑ "Nifedipine - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  10. ↑ Hypertension: management of hypertension in adults in primary care. Clinical guideline CG34. National Institute for Health and Clinical Excellence (NICE). June 2006. ISBN   1-86016-285-1. Archived from the original on 17 June 2007.
  11. ↑ Gelenberg AJ (March 1997). "Nifedipine for MAOI Hypertension? Reversing a Previous Recommendation". Biological Therapies in Psychiatry. Archived from the original on 10 September 2015. Retrieved 22 January 2015– via Dr. Bob's Psychopharmacology Tips.
  12. ↑ Grossman E, Messerli FH, Grodzicki T, Kowey P (1996). "Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies?". JAMA. 276 (16): 1328–1331. doi:10.1001/jama.1996.03540160050032. PMID   8861992.
  13. ↑ Varon J, Marik PE (October 2003). "Clinical review: the management of hypertensive crises". Critical Care. 7 (5): 374–384. doi: 10.1186/cc2351 . PMC   270718 . PMID   12974970.
  14. ↑ Campagnolo DI. "Autonomic Dysreflexia in Spinal Cord Injury". eMedicine. Retrieved 14 July 2011.
  15. ↑ Flenady V, Wojcieszek AM, Papatsonis DN, Stock OM, Murray L, Jardine LA, et al. (June 2014). "Calcium channel blockers for inhibiting preterm labour and birth". The Cochrane Database of Systematic Reviews. 2014 (6): CD002255. doi:10.1002/14651858.CD002255.pub2. PMC   7144737 . PMID   24901312.
  16. ↑ Thompson AE, Pope JE (February 2005). "Calcium channel blockers for primary Raynaud's phenomenon: a meta-analysis". Rheumatology. 44 (2): 145–150. doi: 10.1093/rheumatology/keh390 . PMID   15546967.
  17. ↑ Ezri T, Susmallian S (June 2003). "Topical nifedipine vs. topical glyceryl trinitrate for treatment of chronic anal fissure". Diseases of the Colon and Rectum. 46 (6): 805–808. doi:10.1007/s10350-004-6660-8. PMID   12794583. S2CID   24717470.
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  19. ↑ Bos D, Kapoor A (November 2014). "Update on medical expulsive therapy for distal ureteral stones: Beyond alpha-blockers". Canadian Urological Association Journal = Journal de l'Association des Urologues du Canada. 8 (11–12): 442–445. doi: 10.5489/cuaj.2472 . PMC   4277526 . PMID   25553160.
  20. ↑ Odou P, Ferrari N, Barthélémy C, Brique S, Lhermitte M, Vincent A, et al. (April 2005). "Grapefruit juice-nifedipine interaction: possible involvement of several mechanisms". Journal of Clinical Pharmacy and Therapeutics. 30 (2): 153–158. doi: 10.1111/j.1365-2710.2004.00618.x . PMID   15811168. S2CID   30463290.
  21. ↑ "Nifedipine". NICE. Retrieved 1 April 2021.
  22. ↑ Nifediac package insert, TEVA Pharmaceuticals, Sellersville, Pennsylvania, August 2009.
  23. ↑ Baselt RC (2008). Disposition of Toxic Drugs and Chemicals in Man. Foster City, CA: Biomedical Publications. pp. 1108–1110. ISBN   978-0-9626523-7-0.
  24. ↑ Curtis TM, Scholfield CN (May 2001). "Nifedipine blocks Ca2+ store refilling through a pathway not involving L-type Ca2+ channels in rabbit arteriolar smooth muscle". The Journal of Physiology. 532 (Pt 3): 609–623. doi:10.1111/j.1469-7793.2001.0609e.x. PMC   2278590 . PMID   11313433.
  25. ↑ McDonald TF, Pelzer S, Trautwein W, Pelzer DJ (April 1994). "Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells". Physiological Reviews. 74 (2): 365–507. doi:10.1152/physrev.1994.74.2.365. PMID   8171118.
  26. ↑ Luther JM (September 2014). "Is there a new dawn for selective mineralocorticoid receptor antagonism?". Current Opinion in Nephrology and Hypertension. 23 (5): 456–461. doi:10.1097/MNH.0000000000000051. PMC   4248353 . PMID   24992570.
  27. ↑ Vater W, Kroneberg G, Hoffmeister F, Saller H, Meng K, Oberdorf A, et al. (January 1972). "[Pharmacology of 4-(2'-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (Nifedipine, BAY a 1040)]". Arzneimittel-Forschung (in German). 22 (1): 1–14. PMID   4622472.
  28. ↑ Lichtlen PR (1991). Adalat: A Comprehensive Review. Berlin et al: Springer-Verlag. p. 2. ISBN   3642855008.
  29. 1 2 EP 0047899B2,Hegasy A, Rämsch KD,"Solid pharmaceutical compositions containing nifedipine, and process for their preparation",issued 28 February 1996, assigned to Bayer AG
  30. ↑ "Adalat Retard Tablet". tabletwise.net. Retrieved 29 January 2022.
  31. ↑ "Herzversagen Todesursache - Sterbefälle Sterbeziffern 1980-1997". www.gbe-bund.de. Retrieved 29 January 2022.
  32. ↑ Bletzer S (2 July 2013). Pharma-Unternehmen und Gesundheitsmanagement: Strategische Diversifizierung durch Dienstleistungen (in German). Springer-Verlag. pp. 8, footnote 49. ISBN   978-3-322-99515-5.
  33. ↑ Mey A (2013). Drees N (ed.). "Pharmamarketing: Rx-to-OTC-Switch als strategischer Ansatz im Life-Cycle-Management für pharmazeutische Produkte" (PDF). Erfurter Hefte zum Angewandten Marketing (in German). Erfurt, Deutschland: Fachhochschule Erfurt University of Applied Sciences Wirtschafts-wissenschaften (40): 1–56, esp. 17. Retrieved 8 March 2021– via DB-Thueringen.de.
  34. ↑ "The Otto Bayer Medal". Science Prize for Bayer Employees. 3 January 2022. Retrieved 29 January 2022.
  35. ↑ "Pfizer Found Guilty In Adalat CC Case". The Pharma Letter . London. 4 September 1994. Retrieved 29 January 2022.
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  39. ↑ "Compendium" . Retrieved 10 February 2023.
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