Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Mefloquine Hydrochloride

doi:10.1002/jps.22249

Journal of Pharmaceutical Sciences

Volume 100, Issue 1, January 2011, Pages 11-21

https://doi.org/10.1002/jps.22249 Get rights and content

ABSTRACT

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release solid oral dosage forms containing mefloquine hydrochloride as the only active pharmaceutical ingredient (API) are reviewed. The solubility and permeability data of mefloquine hydrochloride as well as its therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability studies were taken into consideration. Mefloquine hydrochloride is not a highly soluble API. Since no data on permeability are available, it cannot be classified according to the Biopharmaceutics Classification System with certainty. Additionally, several studies in the literature failed to demonstrate BE of existing products. For these reasons, the biowaiver cannot be justified for the approval of new multisource drug products containing mefloquine hydrochloride. However, scale-up and postapproval changes (HHS-FDA SUPAC) levels 1 and 2 and most EU type I variations may be approvable without in vivo BE, using the dissolution tests described in these regulatory documents.

Section snippets

INTRODUCTION

A biowaiver monograph of mefloquine hydrochloride based on literature data together with some additional experimental data is presented. The risks of basing a bioequivalence (BE) assessment on in vitro rather than in vivo study results for the approval of new immediate release (IR) solid oral dosage forms (so-called “biowaiving”) containing mefloquine hydrochloride, including both reformulated products and new multisource drug products, are evaluated under consideration of its biopharmaceutical

Name

Mefloquine²⁵ (INN); mefloquine hydrochloride (INNM). Mefloquine hydrochloride is a 4-quinolinemethanol derivative with the chemical name of DL-erythro-α-2-piperidyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol-hydrochloride.²⁵ Its two enantiomers are (9R,10S)-(+)-α-piperidyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol-hydrochloride and (9S,10R)-(−)-α-piperidyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol-hydrochloride. According to IUPAC nomenclature it is termed (R,S)-erythro

Solubility

The solubility of mefloquine hydrochloride is reported to range from very slightly soluble⁵⁵ to slightly soluble⁵⁶ in water at room temperature. To investigate the solubility properties of mefloquine hydrochloride according to the Biopharmaceutics Classification System (BCS), additional solubility determinations in water and aqueous buffer media were performed.a The solubility data were obtained at 37°C using a standard shake-flask method. The results are shown in Table 1 and demonstrate that

Absorption and Bioavailability

Since intravenous (i.v.) formulations of mefloquine hydrochloride cause severe venous irritation at the injection site, there is no i.v. dosage form of mefloquine hydrochloride available on the market.75., 76., 77. Therefore, it has not been possible to determine the absolute oral BA of mefloquine hydrochloride.²⁹^,³¹^,⁷⁶

The pharmacokinetic properties of mefloquine have been studied by Desjardins et al.⁷⁵ using single oral doses of 250, 500, 1000, and 1500 mg. The results of this study indicate a

Bioequivalence

Several studies have demonstrated that the European mefloquine products Lariam® and Mephaquin® are not bioequivalent.⁵⁸^,⁸³ Weidekamm et al.⁵⁸ performed pharmacokinetic studies of Lariam® and Mephaquin® tablets in 18 healthy volunteers. Statistical evaluation of the pharmacokinetic parameters demonstrated that these two products are not bioequivalent and differences in clinical responses cannot be excluded.⁵⁸ Moreover, a study in 19 Thai patients with acute uncomplicated P. falciparum malaria

Solubility

The solubility studies of mefloquine hydrochloride published in the literature were not performed under the conditions specified for BCS classification. Results from additional, BCS-conforming solubility measurements indicate that the D/S ratios for the maximum available dosage strength (274.09–275 mg mefloquine hydrochloride) lie between 141 and 908 mL over the pH range 1.0–7.5. The highest solubility of mefloquine hydrochloride was measured at pH 4.5. At lower pH conditions, a common-ion

CONCLUSIONS

Due to the lack of reliable permeability data and the failure to meet the highly soluble criterion, mefloquine hydrochloride cannot yet be assigned conclusively to a BCS Class: it could belong to either BCS Class II or IV. Therefore, a biowaiver currently is not justified for new multisource products or for the re-approval of existing drug products after extensive variations in the formulation and/or manufacturing process, that is, SUPAC level 3⁸⁸ or EU type II variations.⁹⁵ Small changes may

ACKNOWLEDGEMENTS

Kik Groot, RIVM, is acknowledged for producing Table 3. We also thank K. Ahmad, S. Hilbert, and R. Roosen for their assistance in the laboratory.

REFERENCES (95)

H. Vogelpoel et al.
Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: Verapamil hydrochloride, propranolol hydrochloride, and atenolol
J Pharm Sci
(2004)
S. Grube et al.
Biowaiver monographs for immediate release solid oral dosage forms: Quinidine sulfate
J Pharm Sci
(2009)
L. Kalantzi et al.
Biowaiver monographs for immediate release solid oral dosage forms: Acetaminophen (paracetamol)
J Pharm Sci
(2006)
G.E. Granero et al.
Biowaiver monographs for immediate release solid oral dosage forms: Acetazolamide
J Pharm Sci
(2008)
J. Arnal et al.
Biowaiver monographs for immediate release solid oral dosage forms: Aciclovir
J Pharm Sci
(2008)
R.H. Manzo et al.
Biowaiver monographs for immediate release solid oral dosage forms: Amitriptyline hydrochloride
J Pharm Sci
(2006)
R.K. Verbeeck et al.
Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: Chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride
J Pharm Sci
(2005)
E. Jantratid et al.
Biowaiver monographs for immediate release solid oral dosage forms: Cimetidine
J Pharm Sci
(2006)
C. Becker et al.
Biowaiver monographs for immediate release solid oral dosage forms: Ethambutol dihydrochloride
J Pharm Sci
(2008)
H. Potthast et al.
Biowaiver monographs for immediate release solid oral dosage forms: Ibuprofen
J Pharm Sci
(2005)

C. Becker et al.

Biowaiver monographs for immediate release solid oral dosage forms: Isoniazid

J Pharm Sci

(2007)

A.G. Stosik et al.

Biowaiver monographs for immediate release solid oral dosage forms: Metoclopramide hydrochloride

J Pharm Sci

(2008)

C. Becker et al.

Biowaiver monographs for immediate release solid oral dosage forms: Pyrazinamide

J Pharm Sci

(2008)

H. Kortejärvi et al.

Biowaiver monographs for immediate release solid oral dosage forms: Ranitidine hydrochloride

J Pharm Sci

(2005)

M. Vogt et al.

Biowaiver monographs for immediate release solid oral dosage forms: Prednisolone

J Pharm Sci

(2007)

M. Vogt et al.

Biowaiver monographs for immediate release solid oral dosage forms: Prednisone

J Pharm Sci

(2007)

C. Becker et al.

Biowaiver monographs for immediate release solid oral dosage forms: Rifampicin

J Pharm Sci

(2009)

H.O. Lobel et al.

Long-term malaria prophylaxis with weekly mefloquine

Lancet

(1993)

J.D. Arthur et al.

Mefloquine prophylaxis

Lancet

(1990)

C. Hennequin et al.

Agranulocytosis during treatment with mefloquine

Lancet

(1991)

E. Van den Enden et al.

Mefloquine-induced Stevens–Johnson syndrome

Lancet

(1991)

P. Lim

Mefloquine hydrochloride

A. Kiss et al.

Solid state investigation of mefloquine hydrochloride

J Pharm Biomed Anal

(1994)

Y.T. Pham et al.

Interactions of racemic mefloquine and its enantiomers with P-glycoprotein in an immortalised rat brain capillary endothelial cell line, GPNT

Biochim Biophys Acta

(2000)

M. Lindenberg et al.

Classification of orally administered drugs on the World Health Organization Model List of Essential Medicines according to the biopharmaceutics classification system

Eur J Pharm Biopharm

(2004)

World Health Organization (WHO)

Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms

Technical Report Series, No 937, 40th Report, Annex 8 of WHO Expert Committee on Specifications for Pharmaceutical Preparations

(2006)

U.S., Department of Health and Human Services, Food and Drug Administration, Center for Evaluation and Research (CDER)

Guidance for Industry: Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a Biopharmaceutics Classification System

(2000)

European Medicines Agency (EMA)

Committee for Proprietary Medicinal Products (CPMP)

Guideline on the Investigation of Bioequivalence—Draft

(2008)

B. Chuasuwan et al.

Biowaiver monographs for immediate release solid oral dosage forms: Diclofenac sodium and diclofenac potassium

J Pharm Sci

(2009)

E. Jantratid et al.

Biowaiver monographs for immediate release solid oral dosage forms: Doxycycline hyclate

J Pharm Sci

(2009)

G.E. Granero et al.

Biowaiver monographs for immediate release solid oral dosage forms: Furosemide

J Pharm Sci

(2009)

International Federation Pharmaceutical (FIP). Special Interest Group on Biopharmaceutics Classification System (BCS)....

Word Health Organization (WHO)

International Nonproprietary Names for pharmaceutical substances—Mefloquine

WHO Chronicle, Vol. 29, No. 3

(1975)

The European Pharmacopoeia (Ph.Eur.)

Pharm. Eur. Kommentar (German), NT 2001—Mefloquinhydrochlorid/Mefloquini hydrochloridum

(2002)

PubChem

PubChem Substance: Mefloquine—Substance Summary

The Merck Index. 2006. 14th ed., Whitehouse Station, NJ,...

A.G. Roche Pharma

Fachinformation Lariam (German). Rote Liste Service GmbH

World Health Organization (WHO)

The use of antimalarial drugs—Part II: 1.5 Mefloquine. Roll Back Malaria/World Health Organisation

A.G. Mepha Pharma

Mephaquin—Product Information for the Medicinal Professionals

C. Crevoisier et al.

Food increases the bioavailability of mefloquine

Eur J Clin Pharmacol

(1997)

N.J. White

Clinical pharmacokinetics of antimalarial drugs

Clin Pharmacokinet

(1985)

S. Sweetman

Martindale: The complete drug reference

(2006)

D. Huzly et al.

Malaria chemoprophylaxis in German tourists: A prospective study on compliance and adverse reactions

J Travel Med

(1996)

P. Schlagenhauf et al.

Neuropsychiatric events and travel: Do antimalarials play a role?

J Travel Med

(2000)

C. Hoebe et al.

Adverse effects and compliance with mefloquine or proguanil antimalarial chemoprophylaxis

Eur J Clin Pharmacol

(1997)

A.C. White et al.

Cutaneous vasculitis associated with mefloquine

Ann Int Med

(1995)

L. Scerri et al.

Mefloquine-associated cutaneous vasculitis

Int J Dermatol

(1993)

Cited by (25)

Idiosyncratic quinoline central nervous system toxicity: Historical insights into the chronic neurological sequelae of mefloquine
2014, International Journal for Parasitology: Drugs and Drug Resistance
Citation Excerpt :
In 2013, European regulators updated the drug’s core safety profile to warn that symptoms of polyneuropathy developing during mefloquine use were associated with risk of an irreversible neurological condition (Bundesinstitut für Arzneimittel und Medizinprodukte, 2013), and FDA updated the U.S. product labeling with a boxed warning that other neurological effects including vertigo and loss of balance could be permanent in some cases (Arznei-Telegramm, 2013b; McGuire and Wilson, 2013). Originally developed by the U.S. military and first licensed in Europe over a quarter century ago by F. Hoffmann-La Roche as Lariam® (Croft, 2007a), the innovator product was recently withdrawn from the U.S. market without explanation (Strauch et al., 2011). Generic formulations of mefloquine remain recommended in the U.S. (Centers for Disease Control and Prevention, 2013), but are decreasingly prescribed for the drug’s original antimalarial indications (LaRocque et al., 2012; Kersgard and Hickey, 2013).
Mefloquine is a quinoline derivative antimalarial which demonstrates promise for the treatment of schistosomiasis. Traditionally employed in prophylaxis and treatment of chloroquine-resistant Plasmodium falciparum malaria, recent changes to the approved European and U.S. product labeling for mefloquine now warn of a risk of permanent and irreversible neurological sequelae including vertigo, loss of balance and symptoms of polyneuropathy. The newly described permanent nature of certain of these neurological effects challenges the conventional belief that they are due merely to the long half-life of mefloquine and its continued presence in the body, and raises new considerations for the rational use of the drug against parasitic disease. In this opinion, it is proposed that many of the reported lasting adverse neurological effects of mefloquine are consistent with the chronic sequelae of a well characterized but idiosyncratic central nervous system (CNS) toxicity syndrome (or toxidrome) common to certain historical antimalarial and antiparasitic quinolines and associated with a risk of permanent neuronal degeneration within specific CNS regions including the brainstem. Issues in the development and licensing of mefloquine are then considered in the context of historical awareness of the idiosyncratic CNS toxicity of related quinoline drugs. It is anticipated that the information presented in this opinion will aid in the future clinical recognition of the mefloquine toxidrome and its chronic sequelae, and in informing improved regulatory evaluation of mefloquine and related quinoline drugs as they are explored for expanded antiparasitic use and for other indications.
The impact of the EMA change in definition of "dose" on the BCS dose-solubility ratio: A review of the biowaiver monographs
2014, Journal of Pharmaceutical Sciences
Citation Excerpt :
The D/S ratio of diclofenac, mefloquine, and rifampicin already exceeded the 250 mL using the 2001 EMEA definition of dose, consistent with their classification according to the US FDA and WHO criteria. Therefore, the increase in the dose associated with the new definition leads to the D/S ratio exceeding the criterion by an even wider margin: the BCS classification of these API is thus not affected.23-26 Although amitriptyline did not meet the criterion for highly soluble at pH 7.5 (US FDA criterion) at the highest dose strength, it had been decided to make a positive biowaiver recommendation based on the high solubility at pH values up to 6.8 and the risk analysis.
The Biopharmaceutics Classification System (BCS) defines the solubility characteristics of an active pharmaceutical substance based on its dose–solubility ratio: for highly soluble drugs this ratio is less than 250 mL over a defined pH range. Prior to the revision of the European Medicines Agency (EMA, formerly EMEA) guideline in 2010, the “dose” in this ratio was consistently defined by the US FDA, the EMA, and the WHO biowaiver guidelines as the highest dosage strength. However, in the revised EMA guideline, the dose is defined as the highest single dose administered according to the Summary of Product Characteristics. The new EMA criterion for highly soluble may be closer to the actual conditions of use, but it is not in line with the dose that would be used in the in vivo bioequivalence study. This paper evaluates the impact on the BCS classification of the active pharmaceutical ingredients of the published biowaiver monographs and discusses the consequences of the possible change in classification on biowaiver recommendations. Using the current definition of dose by the EMA, the biowaiver recommendations for metoclopramide hydrochloride and verapamil hydrochloride are no longer valid according to EMA criteria. For prednisolone and prednisone, a reevaluation of the biowaiver recommendation, taking into account the usual dosing levels, seems appropriate. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:65–70, 2014
Limbic encephalopathy and central vestibulopathy caused by mefloquine: A case report
2012, Travel Medicine and Infectious Disease
Citation Excerpt :
By 2008, following reports of persistent vertigo lasting as long as 12–18 months,11,12 the U.S. product insert was updated to warn that in “a small number of patients, dizziness and loss of balance have been reported to continue for months after mefloquine has been stopped”.13 Notwithstanding continued claims of safety, in 2009 the innovator product (Lariam®, F. Hoffman-La Roche) was withdrawn from the U.S. market,14 and the U.S. military sharply curtailed the use of mefloquine in chemoprophylaxis, returning to a policy of first-line doxycycline use,1 the drug of choice prior to mefloquine's licensure.15 Writing in the 2012 CDC Yellow Book, U.S. military authors conceded that the neuropsychiatric side effects of the drug made “continued routine use of mefloquine less desirable”.16
Mefloquine is a 4-methanolquinoline anti-malarial that in recent years has fallen out of favor for use as chemoprophylaxis against infection with chloroquine-resistant Plasmodium falciparum malaria owing in part to growing concerns of side effects and potential neurotoxicity. Despite over 20 years of licensed use, the pathophysiological mechanisms underlying mefloquine's neuropsychiatric and physical side effects and the clinical significance of the drug's neurotoxicity have remained poorly understood. In this report, an adverse reaction to mefloquine chemoprophylaxis is described characterized by prodromal symptoms of anxiety with subsequent development of psychosis, short-term memory impairment, confusion and personality change accompanied by complaints of disequilibrium and vertigo, with objective findings of central vestibulopathy. It is posited that these effects represent an idiosyncratic neurotoxic syndrome of progressive limbic encephalopathy and multifocal brainstem injury caused by the drug. This case provides insights into the clinical significance of mefloquine neuronal gap junction blockade and neurotoxicity demonstrated in animal models, points to recommendations for the management of affected patients including diagnostic considerations and appropriate referrals, and highlights critical implications for the continued safe use of the medication.
Biowaiver monographs for immediate-release solid oral dosage forms: Primaquine phosphate
2012, Journal of Pharmaceutical Sciences
Citation Excerpt :
The risk–benefit analysis includes a consideration of the probability of an incorrect biowaiver decision as well as the consequences of an incorrect decision in terms of public health and individual patient risks. Biowaiver monographs have already been published for various APIs.1,5–25 These monographs are also available online on the International Pharmaceutical Federation's website (www.fip.org/bcs_monographs).
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release (IR) solid oral dosage forms containing the antimalarial drug primaquine phosphate as the only active pharmaceutical ingredient (API) are reviewed. On the basis of permeability data and solubility studies, primaquine phosphate was found to be “highly soluble” and “highly permeable” API, thus conforming to Class I of the Biopharmaceutical Classification System (BCS). It has a wide therapeutic index. BCS-conform dissolution studies showed the products to be rapidly dissolving. No data pertaining to BE or bioinequivalence of IR primaquine phosphate products could be located in open literature. On the basis of the available data, a biowaiver-procedure-based approval can be recommended for IR solid oral dosage forms of primaquine phosphate, provided the generic product contains excipients present in products already approved by the International Conference on Harmonisation or associated countries in similar amounts and the test and reference products meet the dissolution criteria for “rapidly dissolving” (>85% drug release in 30 min in standard media at pH 1.2, 4.5, and 6.8; similarity factor (f₂) > 50) or “very rapidly dissolving” products (>85% drug release in 15 min in standard media at pH 1.2, 4.5, and 6.8).
Investigating channel blockers for the treatment of multiple sclerosis: Considerations with mefloquine and carbenoxolone
2012, Journal of Neuroimmunology
Mefloquine neurotoxicity and gap junction blockade: Critical insights in drug repositioning
2011, NeuroToxicology

View all citing articles on Scopus

: This article reflects the scientific opinion of the authors and not necessarily the policies of regulating agencies, the International Pharmaceutical Federation (FIP), and the World Health Organization (WHO).

^a: Studies performed at the Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany, using Mefloquine hydrochloride ≥98% pure, lot 060099U00, from Roche Diagnostics GmbH, Mannheim, Germany. No information was available on the polymorphic form.

^b: Studies performed at the Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany, with Lariam, Roche, Germany, Lot B114312 and Mephaquin, Mepha Pharma AG, Switzerland, Lot 0752105.

View full text